CiteULike: jyuh's Saito

Hormonal regulation of organic cation transporter OCT2 expression in rat kidney

Yumiko Urakami — 2008-08-17T16:33:36-00:00

FEBS Letters, Vol. 473, No. 2. (12 May 2000), pp. 173-176.

Rat (r) OCT2 was identified as the second member of the organic cation transporter (OCT) family, and is predominantly expressed in the kidney. We reported previously that rOCT2 was responsible for the gender differences in renal basolateral membrane organic cation transport activity. As renal rOCT2 expression in males is much higher than that in females, we hypothesized that rOCT2 expression may be under the control of sex hormones. Treatment of male and female rats with testosterone significantly increased the expression levels of rOCT2 mRNA and protein in the kidney, whereas estradiol treatment moderately decreased the expression levels of rOCT2. There was no regulation of renal rOCT1 mRNA expression by testosterone or estradiol. Treatment of male and female rats with testosterone significantly stimulated the tetraethylammonium (TEA) accumulation by renal slices, whereas estradiol treatment caused a decrease in the TEA accumulation by slices from male but not female rats. The present findings suggested that testosterone up-regulates renal rOCT2 expression and estradiol moderately down-regulates rOCT2.

Down-regulation of rat organic cation transporter rOCT2 by 5/6 nephrectomy

Lin Ji — 2008-08-17T16:33:03-00:00

Kidney Int, Vol. 62, No. 2. (2002), pp. 514-524.

Regulation of Renal Organic Ion Transporters in Cisplatin-Induced Acute Kidney Injury and Uremia in Rats.

Takafumi Morisaki — 2008-08-12T04:16:09-00:00

Pharmaceutical research (9 July 2008)

PURPOSE: The purpose of this study was to examine the regulation of renal organic ion transporters in cisplatin-induced acute kidney injury (AKI) and its relation with indoxyl sulfate (IS), a uremic toxin. METHODS: The IS concentrations in the serum and kidney were monitored by high-performance liquid chromatography. Uptake of p-aminohippuric acid, estrone-3-sulfate and tetraethylammonium were examined using renal slices. Real-time PCR and immunoblotting were performed to examine the mRNA and protein expression of rOATs, rOCTs and rMATE1 in the kidney, respectively. RESULTS: The serum and renal IS levels were markedly elevated in cisplatin-treated rats. However, this effect was largely reversed by administration of AST-120, an oral charcoal adsorbent. The functions of renal basolateral organic anion and cation transporters were reduced in cisplatin-treated rats. The levels of mRNA and protein corresponding to rOAT1, rOAT3, rOCT2 and rMATE1, but not rOCT1, were depressed in the kidney of cisplatin-treated rats. Administration of AST-120 to cisplatin-treated rats partially restored the function and expression level of these transporters. CONCLUSIONS: Cisplatin-induced AKI causes down-regulation of renal organic ion transporters accompanied by accumulation of serum and renal IS. IS could be involved in the mechanism of down-regulation of rOAT1, rOAT3 and rMATE1 under cisplatin-induced AKI.

Downregulation of organic anion transporters in rat kidney under ischemia/reperfusion-induced acute [corrected] renal failure.

T Matsuzaki — 2008-08-12T04:11:56-00:00

Kidney international, Vol. 71, No. 6. (March 2007), pp. 539-547.

The effect of acute renal failure (ARF) induced by ischemia/reperfusion (I/R) of rat kidney on the expression of organic anion transporters (OATs) was examined. The level of serum indoxyl sulfate (IS), a uremic toxin and substrate of OATs in renal tubules, shows a marked increase with the progression of ARF. However, this increase was significantly attenuated by ingestion of cobalt. The level of mRNA and protein of both rOAT1 and rOAT3 were markedly depressed in the ischemic kidney. The uptake of p-aminohippuric acid (PAH) and estrone sulfate (ES) by renal slices of ischemic rats was significantly reduced compared to control rats. Renal slices taken from ischemic rats treated with cobalt displayed significantly elevated levels of ES uptake. Cobalt intake did not affect PAH uptake, indicating the functional restoration of rOAT3 but not rOAT1. The expression of Na(+)/K(+)-ATPase was markedly depressed in the ischemic kidney, suggesting that the inward Na(+) gradient in renal tubular cells had collapsed, thereby reducing the outward gradient of alpha-ketoglutarate, a driving force of both rOATs. The decreased expression of Na(+)/K(+)-ATPase was significantly restored by cobalt treatment. Our results suggest that the downregulation of renal rOAT1 and rOAT3 could be responsible for the increase in serum IS level of ischemic rats. Cobalt treatment has a significant protective effect on ischemia-induced ARF, being accompanied by the restoration of rOAT3 and/or Na(+)/K(+)-ATPase function.

Possible involvement of organic anion and cation transporters in renal excretion of xanthine derivatives, 3-methylxanthine and enprofylline.

M Nadai — 2008-08-12T04:06:27-00:00

Life sciences, Vol. 81, No. 15. (22 September 2007), pp. 1175-1182.

Whether organic anion and cation transporters are involved in the renal excretion of xanthine derivatives, 3-methylxanthie and enprofylline, remains unclear. In this study, we have investigated the effects of typically predominant substrates for organic anion and cation transporters on the tubular secretion of 3-methylxanthine and enprofylline in rats. In the renal clearance experiments using typical substrates for organic anion transporters, probenecid and p-aminohippurate, probenecid (20 mg/kg), but not p-aminohippurate (100 mg/kg), significantly decreased the renal clearance and clearance ratio of 3-methylxanthine and enprofylline. The typical substrates for organic cation transport systems, tetraethylammonium (30.6 mg/kg) and cimetidine (50 or 100 mg/kg), significantly decreased the renal clearance and clearance ratio of 3-methylxanthine and enprofylline. These results suggest that the renal secretory transport of 3-methylxanthine and enprofylline are mediated by probenecid-, cimetidine- and tetraethylammonium-sensitive transport systems. Uric acid, an organic anion, significantly inhibited the renal secretion of 3-methylxanthine, but not enprofylline, suggesting that the renal tubular transport of 3-methylxanthine is also mediated via uric acid-sensitive transport system. These findings suggest the possibility that both organic anion and cation transporters are, at least, involved in the renal tubular transport of 3-methylxanthine and enprofylline in rats.

High-dimensional and large-scale phenotyping of yeast mutants

Yoshikazu Ohya — 2006-03-16T08:16:13-00:00

PNAS, Vol. 102, No. 52. (27 December 2005), pp. 19015-19020.

One of the most powerful techniques for attributing functions to genes in uni- and multicellular organisms is comprehensive analysis of mutant traits. In this study, systematic and quantitative analyses of mutant traits are achieved in the budding yeast Saccharomyces cerevisiae by investigating morphological phenotypes. Analysis of fluorescent microscopic images of triple-stained cells makes it possible to treat morphological variations as quantitative traits. Deletion of nearly half of the yeast genes not essential for growth affects these morphological traits. Similar morphological phenotypes are caused by deletions of functionally related genes, enabling a functional assignment of a locus to a specific cellular pathway. The high-dimensional phenotypic analysis of defined yeast mutant strains provides another step toward attributing gene function to all of the genes in the yeast genome.

Decoding genes with coexpression networks and metabolomics - 'majority report by precogs'.

K Saito — 2008-08-08T09:37:48-00:00

Trends in plant science, Vol. 13, No. 1. (January 2008), pp. 36-43.

Following the sequencing of whole genomes of model plants, high-throughput decoding of gene function is a major challenge in modern plant biology. In view of remarkable technical advances in transcriptomics and metabolomics, integrated analysis of these 'omics' by data-mining informatics is an excellent tool for prediction and identification of gene function, particularly for genes involved in complicated metabolic pathways. The availability of Arabidopsis public transcriptome datasets containing data of >1000 microarrays reinforces the potential for prediction of gene function by transcriptome coexpression analysis. Here, we review the strategy of combining transcriptome and metabolome as a powerful technology for studying the functional genomics of model plants and also crop and medicinal plants.

Association of predialysis serum bicarbonate levels with risk of mortality and hospitalization in the Dialysis Outcomes and Practice Patterns Study (DOPPS).

J Bommer — 2008-07-03T12:57:44-00:00

American journal of kidney diseases : the official journal of the National Kidney Foundation, Vol. 44, No. 4. (October 2004), pp. 661-671.

BACKGROUND: Experimental and some clinical data suggest that metabolic acidosis contributes to poor nutritional status, a strong predictor for mortality in hemodialysis patients. However, recent cross-sectional studies indicate that severe predialysis metabolic acidosis is associated with a greater normalized protein catabolic rate (nPCR) and greater serum albumin levels. Given this controversy, we analyzed data from the Dialysis Outcomes and Practice Pattern Study (DOPPS) for associations between predialysis serum bicarbonate and albumin concentrations, nPCR, and patient risk for mortality and hospitalization. METHODS: Data from more than 7,000 representative and randomly selected hemodialysis DOPPS patients from France, Germany, Italy, Japan, Spain, the United Kingdom, and the United States were analyzed. Serum bicarbonate (total CO2 ) levels predialysis were corrected to the midweek interdialytic interval. RESULTS: The midweek predialysis serum bicarbonate level averaged 21.9 mEq/L (mmol/L) and correlated inversely with nPCR, serum albumin, and serum phosphorus values. Before and after adjusting for 15 comorbidities, nutrition, and equilibrated Kt/V, a U-curve best represented the association between predialysis serum bicarbonate level and risk for mortality or hospitalization. Patients with midweek predialysis serum bicarbonate levels of 20.1 to 21.0 mEq/L (mmol/L) faced the lowest risk for mortality, whereas those with bicarbonate levels of 21.1 to 22.0 mEq/L faced the lowest risk for hospitalization. Both high (>27 mEq/L) and low (< or =17 mEq/L) serum bicarbonate levels were associated with increased risk for mortality and hospitalization. CONCLUSION: Moderate predialysis acidosis seems to be associated with better nutritional status and lower relative risk for mortality or hospitalization than is observed in patients with normal ranges of midweek predialysis serum bicarbonate concentration (approximately 24 mEq/L) or severe acidosis (<16 mEq/L).

The organization and financing of end-stage renal disease treatment in Japan.

S Fukuhara — 2008-06-28T07:25:37-00:00

International journal of health care finance and economics, Vol. 7, No. 2-3. (September 2007), pp. 217-231.

End-stage renal disease (ESRD) affects 230,000 Japanese, with about 36,000 cases diagnosed each year. Recent increases in ESRD incidence are attributed mainly to increases in diabetes and a rapidly aging population. Renal transplantation is rare in Japan. In private dialysis clinics, the majority of treatment costs are paid as fixed fees per session and the rest are fee for service. Payments for hospital-based dialysis are either fee-for-service or diagnosis-related. Dialysis is widely available, but reimbursement rates have recently been reduced. Clinical outcomes of dialysis are better in Japan than in other countries, but this may change given recent ESRD cost containment policies.

High alkaline phosphatase levels in hemodialysis patients are associated with higher risk of hospitalization and death.

Margaret J Blayney — 2008-06-26T06:00:01-00:00

Kidney international (11 June 2008)

We evaluated risks associated with elevated alkaline phosphatase in hemodialysis patients using longitudinal data from the Dialysis Outcomes and Practice Patterns Study, a prospective observational study of hemodialysis patients in 12 countries. Alkaline phosphatase levels were normalized by the upper limit of the laboratory-reported reference range. Cause-specific hospitalization and mortality risks were evaluated using Cox proportional hazards models, stratified by region and adjusted for phosphorus, calcium, albumin, parathyroid hormone, case mix, and numerous comorbidities. The odds of high normalized alkaline phosphatase were increased twofold in the United States in comparison to Japan. Elevations of normalized alkaline phosphatase were significantly associated with several comorbid conditions, increased fractures, parathyroidectomy, risk of hospitalization due to major adverse cardiac events, higher all-cause cardiovascular, and infection-related mortality risk. Our results also show that elevated serum normalized alkaline phosphatase was associated with higher risks of hospitalization and death in hemodialysis patients, independent of calcium, phosphorus, and parathyroid hormone levels.Kidney International advance online publication, 11 June 2008; doi:10.1038/ki.2008.248.

Lack of appetite in haemodialysis patients--associations with patient characteristics, indicators of nutritional status and outcomes in the international DOPPS.

AA Lopes — 2008-06-23T10:46:53-00:00

Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association, Vol. 22, No. 12. (December 2007), pp. 3538-3546.

BACKGROUND: Identification of haemodialysis patients with problems related to lack of appetite should help prevent adverse outcomes. We studied whether a single question about being bothered by lack of appetite within the prior 4 weeks is related to nutritional status, inflammation and risks of death and hospitalization. Additionally, we assessed associations of lack of appetite with depression, dialysis dose and length of haemodialysis. METHODS: This study is an analysis of baseline and longitudinal data from 14 406 patients enrolled in the Dialysis Outcomes and Practice Pattern Study. Cox regression was used to assess whether the degree (not, somewhat, moderately, very much, extremely) that patients were bothered by lack of appetite is an independent predictor of death and hospitalization. Logistic regression was used to identify baseline characteristics associated with being bothered by lack of appetite. RESULTS: The risk of death was more than 2-fold higher [relative risk (RR) = 2.23; 95% confidence interval (CI) = 1.90-2.62] and the risk of hospitalization 33% higher (RR = 1.33; 95% CI = 1.19-1.48) among patients extremely bothered, compared with not bothered, by lack of appetite. These associations followed a dose-response fashion and remained statistically significant after adjustments for 14 comorbidities. Depression, shorter haemodialysis session, hypoalbuminaemia, lower concentration of serum creatinine and normalized protein catabolic rate, lower body mass index and higher leucocyte and neutrophil counts were independently associated with higher odds of being bothered by lack of appetite. CONCLUSIONS: The data suggest that a single question about lack of appetite helps identify haemodialysis patients with poorer nutritional status, inflammation, depression and higher risks of hospitalization and death. The study calls attention to a possible beneficial effect of longer haemodialysis on appetite.

Association of mineral metabolism factors with all-cause and cardiovascular mortality in hemodialysis patients: The Japan dialysis outcomes and practice patterns study

Naoki Kimata — 2007-06-19T01:26:17-00:00

Hemodialysis International, Vol. 11, No. 3. (July 2007), pp. 340-348.

Innate immunity induced by composition-dependent RIG-I recognition of hepatitis C virus RNA

Takeshi Saito — 2008-06-12T04:36:13-00:00

Nature (11 June 2008)

Regulation of innate immunity against hepatitis C virus infection.

T Saito — 2008-06-14T03:52:20-00:00

Hepatology research : the official journal of the Japan Society of Hepatology, Vol. 38, No. 2. (9 January 2008), pp. 115-122.

Chronic hepatitis C virus (HCV) infection is a global public health problem. HCV infection is treated with type I interferon (IFN), a natural product that is produced by cells during virus infection as a result of innate immune signaling events. The secreted IFN alert the surrounding cells to turn on an "antiviral state" that resists infection. In general, the role of innate immune response is to suppress viral replication and to induce cytokines and other factors that promote adaptive immunity and the resolution of infection. The mechanisms by which the innate immune response and IFN actions limit HCV infection are not well defined, but are likely to involve the function of specific IFN-stimulated genes. HCV also copesintensively with immune responses in order to establish persistent infection. Recent studies reveal that a other viruses use similar tactics to regulate the antiviral innate immune response. In the case of HCV, innate immune signaling is strictly controlled by the viral NS3/4A protease, resulting in the disruption of IFN production. Here, we summarize the current understanding of how HCV evades the innate immune system.

Adrenomedullin inhibits connective tissue growth factor expression, extracellular signal-regulated kinase activation and renal fibrosis.

T Nagae — 2008-06-06T04:25:59-00:00

Kidney international (9 April 2008)

Systemic administration of the potent vasodilating peptide adrenomedullin reduces cardiac and renal fibrosis in hypertensive animals. Here, we investigated the effects of kidney-specific adrenomedullin gene delivery in normotensive rats after unilateral ureteral obstruction, an established model of renal tubulointerstitial fibrosis. Overexpression of exogenous adrenomedullin in the renal interstitium following ureteral obstruction significantly prevented fibrosis and proliferation of tubular and interstitial cells. In this model, there is upregulation of connective tissue growth factor (CTGF) mRNA expression and extracellular signal-regulated kinase (ERK) phosphorylation, and adrenomedullin overexpression suppressed both of these activities without altering the blood pressure. In NRK-49F renal fibroblasts, adrenomedullin reduced transforming growth factor-beta-induced CTGF and fibronectin mRNA upregulation through the cyclic AMP/protein kinase A signaling pathway, and suppressed ERK phosphorylation and cell proliferation. In the kidneys with an obstructed ureter, adrenomedullin receptor gene expression was upregulated along with cyclic AMP production in kidney slices. The latter effect was partially blocked by a neutralizing antibody to adrenomedullin, indicating that an endogenous peptide-receptor system was activated. Our results show that overexpression of exogenous adrenomedullin in the ureteral-obstructed kidney prevents tubulointerstitial fibrosis and cell proliferation through the cyclic AMP-mediated decrease of CTGF induction and ERK phosphorylation.Kidney International advance online publication, 9 April 2008; doi:10.1038/ki.2008.98.

Prediction of corticosteroid responsiveness based on fibroblast-specific protein 1 (FSP1) in patients with IgA nephropathy.

Koji Harada — 2008-06-06T02:37:38-00:00

Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association (7 May 2008)

BACKGROUND: Corticosteroids are frequently used to treat patients with active IgA nephropathy (IgAN); however, there have been few reports describing factors that are predictive of the response to corticosteroid treatment. Purpose. The purpose of this study is to determine the extent to which fibroblast-specific protein 1-positive (FSP1(+)) cells are predictive of corticosteroid responsiveness in patients with IgAN. Patients and Method. Fifty biopsy-proven IgAN patients who received corticosteroid therapy were enrolled and followed for 7.1 +/- 3.0 years. FSP1(+) cells were identified using an anti-FSP1 antibody. Result. Twelve patients showed progression of renal impairment or no reduction of urinary protein (non-responders) after steroid therapy. In the remaining 38 patients, renal function was stable during follow-up, and their urinary protein declined to <1.0 g/day (responders). Serum creatinine, estimated GFR, severity of mesangial proliferation, percent glomerulosclerosis/total glomeruli, extent of interstitial damage and FSP1(+) cell number were all significantly higher in non-responders than in responders. Cox regression analysis using two covariates with every possible combination of factors indicated that FSP1(+) cell number was the strongest and most significant predictor of corticosteroid responsiveness. When IgAN patients had >32.6 FSP1(+) cells/HPF at diagnosis, they were the more likely to show steroid resistance. CONCLUSION: FSP1(+) cell number can serve as an excellent predictor of corticosteroid responsiveness in patients with IgAN.

Critical Role of Virion-Associated Cholesterol and Sphingolipid in Hepatitis C Virus Infection

Hideki Aizaki — 2008-05-30T03:52:57-00:00

J. Virol., Vol. 82, No. 12. (15 June 2008), pp. 5715-5724.

In this study, we establish that cholesterol and sphingolipid associated with hepatitis C virus (HCV) particles are important for virion maturation and infectivity. In a recently developed culture system enabling study of the complete life cycle of HCV, mature virions were enriched with cholesterol as assessed by the molar ratio of cholesterol to phospholipid in virion and cell membranes. Depletion of cholesterol from the virus or hydrolysis of virion-associated sphingomyelin almost completely abolished HCV infectivity. Supplementation of cholesterol-depleted virus with exogenous cholesterol enhanced infectivity to a level equivalent to that of the untreated control. Cholesterol-depleted or sphingomyelin-hydrolyzed virus had markedly defective internalization, but no influence on cell attachment was observed. Significant portions of HCV structural proteins partitioned into cellular detergent-resistant, lipid-raft-like membranes. Combined with the observation that inhibitors of the sphingolipid biosynthetic pathway block virion production, but not RNA accumulation, in a JFH-1 isolate, our findings suggest that alteration of the lipid composition of HCV particles might be a useful approach in the design of anti-HCV therapy. 10.1128/JVI.02530-07

Cell system ontology: representation for modeling, visualizing, and simulating biological pathways.

E Jeong — 2008-05-24T03:38:15-00:00

In silico biology, Vol. 7, No. 6. (2007), pp. 623-638.

With the rapidly accumulating knowledge of biological entities and networks, there is a growing need for a general framework to understand this information at a system level. In order to understand life as system, a formal description of system dynamics with semantic validation will be necessary. Within the context of biological pathways, several formats have been proposed, e.g., SBML, CellML, and BioPAX. Unfortunately, these formats lack the formal definitions of each term or fail to capture the system dynamics behavior. Thus, we have developed a new system dynamics centered ontology called Cell System Ontology (CSO). As an exchange format, the ontology is implemented in the Web Ontology Language (OWL), which enables semantic validation and automatic reasoning to check the consistency of biological pathway models. The features of CSO are as follows: (1) manipulation of different levels of granularity and abstraction of pathways, e.g., metabolic pathways, regulatory pathways, signal transduction pathways, and cell-cell interactions; (2) capture of both quantitative and qualitative aspects of biological function by using hybrid functional Petri net with extension (HFPNe); and (3) encoding of biological pathway data related to visualization and simulation, as well as modeling. The new ontology also predefines mature core vocabulary, which will be necessary for creating models with system dynamics. In addition, each of the core terms has at least one standard icon for easy modeling and accelerating the exchangeability among applications. In order to demonstrate the potential of CSO-based pathway modeling, visualization, and simulation, we present an HFPNe model for the ASEL and ASER regulatory networks in Caenorhabditis elegans.

Increased urinary levels of CXCL5, CXCL8 and CXCL9 in patients with Type 2 diabetic nephropathy.

Mayumi Higurashi — 2008-05-23T13:56:12-00:00

Journal of diabetes and its complications (29 January 2008)

CXC chemokines are particularly significant for leukocyte infiltration in inflammatory diseases. Recent reports have shown that inflammation is one of potential pathogenic mechanisms for diabetic nephropathy. However, information on inflammation related with CXC chemokines in human Type 2 diabetic nephropathy still remains scarce. We measured urinary and serum levels of three CXC chemokines, CXCL5, CXCL8 and CXCL9, in 45 Type 2 diabetic patients (DM), 42 primary renal disease (PRD) patients and 22 healthy controls by enzyme-linked immunosorbent assay. Urinary levels of CXCL5, CXCL8 and CXCL9 in DM were significantly elevated compared to those in controls (P<.0001, P<.01, P<.001; respectively). They increased consistent with urinary albumin excretion rate (UAER) and correlated with UAER in partial correlation analyses (r=0.41, P<.01; r=0.40, P<.01; r=0.45, P<.01; respectively). Urinary levels of CXCL5 in DM were significantly interrelated to HbA(1c) (r=0.42, P<.01). On the other hand, PRD showed significant increased levels of urinary CXCL8 and CXCL9 compared to controls (P<.001, P<.01; respectively), and so did PRD as UAER increased. However, there were no significant elevations of urinary levels of CXCL5 in PRD in spite of the increased UAER. We found significant associations of UAER in DM with diabetes duration, 1/serum creatinine, urinary CXCL5 (adjusted R(2)=0.67, P<.0001) or CXCL9 (adjusted R(2)=0.69, P<.0001) in a stepwise multiple regression analysis. These results suggest that these three CXC chemokines may be involved in the progression of human Type 2 diabetic nephropathy and that CXCL5 may be of use for telling diabetic nephropathy from primary renal diseases.

Prevalence of primary aldosteronism: should we screen for primary aldosteronism before treating hypertensive patients with medication?

T Nishikawa — 2008-05-13T02:35:16-00:00

Endocrine journal, Vol. 54, No. 4. (August 2007), pp. 487-495.

The present review examines various reports describing prevalence of primary aldosteronism (PA) among hypertensives and the screening method of PA to better understand the current concepts used for diagnosing and managing PA among clinicians as well as specialists. Here, we describe and compare the prevalence of PA in Japan, which is well known to induce various vascular complications due to hyperaldosteronemia, resulting in cerebral infarction, myocardial infarction and renal failure, with that in another Asian area, US, European countries, Australia and Africa. The incidence rates for PA among hypertensives were recently reported to be widely raged between 3.2% and 20%. Those discrepancies are due in part to the completely different characteristics of the starting subjects used for studying the prevalence. Moreover, the criteria for screening PA among hypertensives, including aldosterone-renin ratio (ARR), and confirmatory tests for definitely diagnosing PA, such as saline infusion test are varied. We had already reported that a diagnosis of PA was made in 61 (6%) of the 1,020 hypertensive patients during the past five years, from 1995 until 1999. In our study, only 18% of the patients showed a serum K level of 3.3 mEq/l or less. Thus, many clinicians seem to misdiagnose PA as essential hypertension, because of absence of hypokalemia. Finally, we describe highlight key evidence for optimal methods for screening and definitely diagnosing PA among hypertensive patients in order to avoid misjudgment before or after treating hypertensive patients.

Determination of plasma and urinary angiotensinogen levels in rodents by newly developed ELISA

Hiroyuki Kobori — 2008-05-02T10:12:41-00:00

Am J Physiol Renal Physiol, Vol. 294, No. 5. (1 May 2008), pp. F1257-1263.

We recently reported that urinary excretion rates of angiotensinogen provide a specific index of the intrarenal renin-angiotensin system status in angiotensin II-dependent hypertensive rats. Angiotensinogen concentrations in mouse plasma are thought to be much lower than those in rat plasma; however, detailed information is deficient due to lack of direct quantitative measurements of rodent angiotensinogen. To elucidate this issue, we have developed a quantitative method for measurement of rodent angiotensinogen using a sandwich-type ELISA. The standard curve for mouse and rat angiotensinogen exhibited a high linearity at 0.16-10 and 0.08-5 ng/ml, respectively, with correlation coefficients >0.99. While plasma angiotensinogen concentrations of male high serum IgA (HIGA) mice (IgA nephritis model animals, 1,308 +/- 47 ng/ml; n = 10) were lower than those of control BALB/c mice (1,620 +/- 384; n = 12), urinary angiotensinogen concentrations of HIGA mice (14.6 +/- 1.5 ng/ml; n = 34) were higher than those of BALB/c mice (4.6 +/- 0.1; n = 2). In a similar manner, while plasma angiotensinogen concentrations of Zucker diabetic fatty (ZDF) obese rats (type 2 diabetic model animals, 1,789 +/- 50 ng/ml; n = 5) were lower than those of control ZDF lean rats (2,296 +/- 47; n = 5), urinary angiotensinogen concentrations of ZDF obese rats (88.2 +/- 11.4 ng/ml; n = 15) were higher than those of ZDF lean rats (31.3 +/- 1.9; n = 15). These data indicate that plasma and urinary angiotensinogen concentrations are less in mice than rats. However, these data suggest that urinary angiotensinogen levels are different from plasma angiotensinogen levels in rodents. The development of rodent angiotensinogen ELISA allows quantitative comparisons in mouse and rat angiotensinogen levels in models of hypertension and cardiovascular and kidney diseases. 10.1152/ajprenal.00588.2007

Chimeric DNA-RNA hammerhead ribozyme targeting transforming growth factor-beta1 mRNA ameliorates renal injury in hypertensive rats.

Y Tahira — 2008-04-27T16:36:48-00:00

Journal of hypertension, Vol. 25, No. 3. (March 2007), pp. 671-678.

OBJECTIVE: Transforming growth factor (TGF)-beta is a critical factor in the progression of renal injury, regardless of the primary etiology. Such injury is characterized by glomerular sclerosis and tubulointerstitial fibrosis. To develop a ribozyme-based therapy for progressive renal diseases, we examined the effects of chimeric DNA-RNA hammerhead ribozyme targeting TGF-beta1 mRNA on glomerulosclerosis in salt-loaded, stroke-prone spontaneously hypertensive rats (SHR-SP) and salt-sensitive Dahl (Dahl-S) rats. METHODS: The chimeric DNA-RNA ribozyme to TGF-beta1 was delivered by polyethylenimine to cultured mesangial cells from SHR-SP in vitro and to glomeruli in SHR-SP in vivo. The chimeric ribozyme reduced expression of TGF-beta1 mRNA and protein, which was accompanied by inhibition of expression of extracellular matrix molecules such as fibronectin and collagen type I in mesangial cells from SHR-SP in vitro. RESULTS: One intraperitoneal injection of 200 microg of chimeric DNA-RNA ribozyme to TGF-beta1 in vivo markedly ameliorated thickening of capillary artery walls and glomerulosclerosis in salt-loaded SHR-SP and Dahl-S rats without a reduction in blood pressure. The chimeric ribozyme reduced expression of TGF-beta1 and connective tissue growth factor (CTGF) mRNAs in renal cortex in salt-loaded Dahl-S rats. Chimeric ribozyme to TGF-beta1 significantly reduced levels of protein in urine in the Dahl-S rats. CONCLUSION: These results suggest that chimeric DNA-RNA ribozyme to TGF-beta1 may be useful as a gene therapy for progressive tissue injury in a wide variety of renal diseases, including hypertensive nephrosclerosis.

Fibroblast-specific protein 1 is a specific prognostic marker for renal survival in patients with IgAN.

Y Nishitani — 2008-04-21T10:22:25-00:00

Kidney international, Vol. 68, No. 3. (September 2005), pp. 1078-1085.

BACKGROUND: There is little direct evidence that fibroblasts are involved in the progression of the renal interstitial fibrosis in human glomerulonephritis. With the availability of a new specific marker for fibroblasts, we determined the presence of fibroblasts in kidneys with IgA nephropathy (IgAN) and correlated their numbers with various clinical parameters. In particular, we also prospectively asked if the number of fibroblasts in the renal interstitium correlates with prognosis. METHODS: Cells positive for fibroblast-specific protein 1 (FSP1) were localized in renal biopsy specimens using immunohistochemistry with anti-FSP1 antibody. Clinical features were analyzed by one-way analysis of variance (ANOVA) with the Bonferroni correction. To assess the prognostic impact of the number of FSP1+ fibroblasts on renal survival in 142 patients with normal serum creatinine, the relationship between covariates to renal survival were evaluated univariately using the log-rank test and multivariately using Cox proportional hazards. RESULTS: Fibroblasts identified by their expression of FSP1 accumulate in areas showing severe interstitial fibrosis. Some tubular epithelial cells undergoing epithelial-mesenchymal transition (EMT) in fibrotic areas also express FSP1. Numbers of FSP1+ fibroblasts directly correlate with serum creatinine (r = 0.74, P < 0.0001) and inversely correlate with estimated creatinine clearance (r = -0.54, P < 0.0001), and by multivariate analysis, the clinical factors influencing renal survival are urinary protein excretion [> or = 1.0 g/day, relative risk (RR) = 4.20, P= 0.032], hypertension (RR 5.85, P = 0.0027), and > or = 20 FSP1+ fibroblasts per high power field (HPF) (RR 7.39, P = 0.0015). Staining for FSP1+ fibroblasts is largely nonoverlapping with alpha-smooth muscle actin+ (alpha-SMA) cells in the interstitium. CONCLUSION: The target protein FSP1 identifies human fibroblasts and tubular epithelium undergoing EMT, and distinguishes them from the diaspora of alpha-SMA+ vascular smooth muscle cells. FSP1+ fibroblasts are critically related to the progression of IgAN; consequently, staining FSP1 in renal biopsy specimens provides a valuable histologic index of progression.

Cadmium-induced renal dysfunction and mortality in two cohorts: disappearance of the association in a generation born later.

K Arisawa — 2008-03-04T09:20:40-00:00

Toxicol Lett, Vol. 169, No. 3. (30 March 2007), pp. 214-221.

The association between exposure to environmental cadmium and mortality was investigated in two cohorts. The study population consisted of 275 (cohort I) and 329 (cohort II) residents (aged >or=40 years) in a cadmium-polluted area, Nagasaki Prefecture, Japan, who had participated in health surveys conducted in 1982 and 1992, respectively. The follow-up period extended from 1982 or 1992 to 2005. In the study area, the dietary cadmium intake had decreased after 1980-1983 because of the restoration of cadmium-polluted paddy fields. In cohort I, the mortality rate among those with urinary beta2-microglobulin (beta2-MG) concentration >or=1000 microg/g creatinine (cr.) was 1.41 times higher than the regional reference rate (95% confidence interval [CI] 1.07-1.83). After adjusting for age and other variables, in men, urinary N-acetyl-beta-D-glucosaminidase, and in women, serum creatinine, beta2-MG clearance, and urinary beta2-MG were significantly associated with increased mortality. However, in cohort II, urinary beta2-MG or total protein was not significantly associated with survival. These findings indicate that cadmium-induced renal dysfunction was a significant predictor of mortality, but that such an association is disappearing, probably because of the selective loss of advanced cases and reduced exposure and body burden.

Cause-specific mortality and cancer incidence rates in relation to urinary beta2-microglobulin: 23-year follow-up study in a cadmium-polluted area.

K Arisawa — 2008-03-04T09:16:09-00:00

Toxicol Lett, Vol. 173, No. 3. (28 September 2007), pp. 168-174.

A longitudinal study was performed to investigate the associations of exposure to environmental cadmium (Cd) with cause-specific mortality and cancer incidence rates. The study population comprised 275 adults living in a Cd-polluted area, Nagasaki Prefecture, Japan. The follow-up period extended from 1982 to 2005 for the analysis of cancer mortality, and from 1985 to 2002 for the analysis of cancer incidence. In the study area, the daily Cd intake from foods had decreased after 1980-1983 because of the restoration of Cd-polluted rice fields. The mortality rate among those with urinary beta2-microglobulin (U-beta2M)>/=1000 microg/g creatinine was significantly higher than that of the Japanese population for death from causes other than cancer, but not for cancers (177 at the 95% confidence interval [CI] 94-303). From analysis within the Cd-polluted area, the age-adjusted rate ratio of cancer deaths associated with increased U-beta2M was 2.58 (95% CI 1.25-5.36). The incidence rate of cancer among those with U-beta2M>/=1000 microg/g creatinine was 1.38 (95% CI 0.69-2.47) times that of the regional reference rate. Within the Cd-polluted area, the age-adjusted rate ratio of developing cancer associated with high U-beta2M was 1.79 (95% CI 0.84-3.82). In summary, there was a significant association between U-beta2M excretion and cancer mortality. However, there was neither a significantly increased standardized incidence ratio of cancer, nor significant relationship between U-beta2M and cancer incidence rate, though the point estimates were higher than unity. Continued follow-up and investigation of a larger cohort may be required before drawing a conclusion for the association between exposure to environmental Cd and cancer risk.

Epidemiologic and clinical factors associated with chronic kidney disease among Asian Americans and Native Hawaiians.

MK Mau — 2008-02-13T07:12:11-00:00

Ethn Health, Vol. 12, No. 2. (April 2007), pp. 111-127.

OBJECTIVE: To examine the association between key susceptibility factors and measures of chronic kidney disease in Asian American and Native Hawaiian participants enrolled in the Hawai'i site of the national Kidney Early Evaluation Program (KEEP-2) study community screening program. DESIGN: In 2001-2003, 793 participants from five ethnic groups (Japanese, Native Hawaii an, Chinese, Filipino and Caucasian) were enrolled in the Hawai'i KEEP-2 program. Odds ratios were used as the measure of association and were computed using unconditional logistic regression. Renal susceptibility factors for chronic kidney disease were included in a multivariable model if found to be statistically significant in univariate analysis. The proportion of Hawai'i KEEP-2 study participants manifesting various clinical characteristics were compared by ethnicity with Japanese as the referent group. RESULTS: Significant ethnic differences in the occurrence of chronic kidney disease were found, with Japanese having the lowest occurrence of chronic kidney disease (18%) and Native Hawaiians the highest (40%). Within each ethnic group, the occurrence of chronic kidney disease was associated with a different ethnic-specific clustering of susceptibility factors. Hypertension was associated with chronic kidney disease among four of the five ethnic groups: Japanese, Caucasian, Native Hawaiian and Filipino. Overweight was associated with a decreased occurrence of chronic kidney disease among Caucasians, while diabetes and lower educational attainment were associated with increased occurrence of chronic kidney disease among Native Hawaiians. For Filipinos, diabetes and age 65 years and older were both associated with an increased occurrence for chronic kidney disease while lower educational attainment was associated with a reduced occurrence of chronic kidney disease. Among Chinese, no factors were significantly associated with chronic kidney disease, although trends for all factors paralleled those of the overall study group. CONCLUSIONS: The occurrence of chronic kidney disease in the Hawai'i KEEP-2 study was nearly fourfold greater compared with the general US population. The clustering of susceptibility factors for chronic kidney disease occurrence was found to differ for all five ethnic groups.

Overexpression of connective tissue growth factor in podocytes worsens diabetic nephropathy in mice

H Yokoi — 2008-02-04T02:52:17-00:00

Kidney Int, Vol. 73, No. 4. (12 December 2007), pp. 446-455.

Troglitazone improves endothelial function and augments renal klotho mRNA expression in Otsuka Long-Evans Tokushima Fatty (OLETF) rats with multiple atherogenic risk factors.

T Yamagishi — 2008-01-28T04:04:01-00:00

Hypertens Res, Vol. 24, No. 6. (November 2001), pp. 705-709.

Targeted disruption of the klotho gene induces multiple phenotypes characteristic of human aging, including arteriosclerosis, pulmonary emphysema and osteoporosis. Moreover, we previously observed that insufficient klotho expression in mice leads to endothelial dysfunction. In the present study, we used Otsuka Long-Evans Tokushima Fatty (OLETF) rats, which exhibit hypertension, obesity, severe hyperglycemia and hypertriglyceridemia, and are thus considered an animal model of atherogenic disease, to test the effects of oral administration of troglitazone (200 mg/kg) on renal klotho mRNA expression and endothelial function. Systolic blood pressure, body weight, plasma glucose and triglyceride levels were all significantly higher in 30-week-old OLETF rats than in controls (LETO; Long-Evans Tokushima Otsuka) (p<0.05, n=7). In addition, endothelium-dependent relaxation of the aorta in response to 10(-5) M acetylcholine was significantly attenuated in OLETF rats (p<0.05, n=7), as was renal expression of klotho mRNA. Administration of troglitazone for 10 weeks significantly reduced systolic blood pressure, plasma glucose and triglyceride levels in OLETF rats, while augmenting endothelium-dependent aortic relaxation and renal klotho mRNA expression. These findings suggest that troglitazone protects the vascular endothelium against damage caused by the presence of multiple atherogenic factors.

Downregulation of the Klotho gene in the kidney under sustained circulatory stress in rats.

H Aizawa — 2008-01-28T04:03:41-00:00

Biochem Biophys Res Commun, Vol. 249, No. 3. (28 August 1998), pp. 865-871.

We recently reported the isolation of the klotho gene, which in predominantly expressed in the kidney and involved in human aging phenotypes. In our previous studies, we demonstrated that the Klotho protein or its metabolites may possibly function as humoral factor(s) and protect against endothelial dysfunction because acetylcholine-mediated NO production in arteries was impaired in heterozygous klotho deficient mice (kl/+). However, the pathophysiological significance of the Klotho protein has not been clarified yet. In the present study, we examined expression of the klotho gene in the kidney of the following rat models for human diseases: (1) spontaneously hypertensive rat, (2) deoxycorticosterone acetate-salt hypertensive rat, (3) 5/6 nephrectomized rat, (4) non-insulin-dependent diabetes mellitus rat (the Otsuka Long-Evans Tokushima Fatty rat), and (5) rat with acute myocardial infarction. The expression levels of klotho mRNA in the kidney in these models were significantly lower than controls except for MI rats. This is the first report showing the expression of the klotho gene in the kidney is regulated under sustained circulatory stress such as long-term hypertension, diabetes mellitus, and chronic renal failure.

Regulation of Src homology 2-containing protein tyrosine phosphatase by advanced glycation end products: the role on atherosclerosis in diabetes.

N Seki — 2008-01-26T09:52:17-00:00

Metabolism, Vol. 56, No. 11. (November 2007), pp. 1591-1598.

Advanced glycation end products (AGEs), among the most important causes of atherosclerosis in diabetes mellitus, stimulate the proliferation of smooth muscle cells (SMCs). Smooth muscle cells are central in the formation of atherosclerotic lesions, where they show both increased migration and accelerated proliferation. In investigating how AGEs stimulate SMC proliferation, we focused on protein tyrosine phosphatase, especially Src homology 2-containing protein tyrosine phosphatase (SHP2), which is considered important in regulating cell proliferation. Advanced glycation end products increased activity of SHP2 in the membrane fraction of rat aortic SMCs compared with control bovine serum albumin (P < .05). Upon characterizing the genomic and promoter structure of SHP2, we detected nuclear factor-kappaB (NF-kappaB) binding sites in the promoter area. Advanced glycation end product stimulation increased luciferase activity in cells transfected with SHP2 promoter region including NF-kappaB binding sites (P < .05) and increased SHP2 expression (P < .05). These data indicate that AGE stimulation appears to activate NF-kappaB. Activated NF-kappaB binds to sites on the SHP2 promoter, resulting in increased SHP2 expression, SHP2 activity, and, ultimately, SMC proliferation. It suggests that AGE stimulation induces SMC proliferation via SHP2, underscoring the importance of control of AGE for suppressing macroangiopathy in diabetes mellitus.

Genetically distinct and clinically relevant classification of hepatocellular carcinoma: putative therapeutic targets.

H Katoh — 2008-01-25T02:03:17-00:00

Gastroenterology, Vol. 133, No. 5. (November 2007), pp. 1475-1486.

BACKGROUND & AIMS: The biological aggressiveness of hepatocellular carcinoma (HCC) and the lack of optimal therapeutic strategies have rendered the disease a major challenge. Highly heterogeneous genetic alteration profiles of HCC have made it difficult to identify effective tailor-made molecular therapeutic targets. Therefore, classification of HCC into genetically homogeneous subclasses would be of great worth to develop novel therapeutic strategies. METHODS: We clarified genome-scale chromosomal copy number alteration profiles and mutational statuses of p53 and beta-catenin in 87 HCC tumors. We investigated the possibility that HCC might be classifiable into a number of homogeneous subclasses based solely on their genetic alteration profiles. We also explored putative molecular therapeutic targets specific for each HCC subgroup. RESULTS: Unsupervised hierarchical cluster analysis based on chromosomal alteration profiles suggested that HCCs with heterogeneous genetic backgrounds are divisible into homogeneous subclasses that are highly associated with a range of clinicopathologic features of the tumors and moreover with clinical outcomes of the patients (P < .05). These genetically homogeneous subclasses could be characterized distinctively by pathognomonic chromosomal amplifications (eg, c-Myc-induced HCC, 6p/1q-amplified HCC, and 17q-amplified HCC). An in vitro experiment raised a possibility that Rapamycin would significantly inhibit the proliferative activities of HCCs with 17q amplification. CONCLUSIONS: HCC is composed of several genetically homogeneous subclasses, each of which harbors characteristic genetic alterations that can be putative tailor-made molecular therapeutic targets for HCCs with specific genetic backgrounds. Our results offer an opportunity for developing novel individualized therapeutic modalities for distinctive genome types of HCC.

Role of megalin in endocytosis of advanced glycation end products: implications for a novel protein binding to both megalin and advanced glycation end products.

A Saito — 2008-01-14T11:55:42-00:00

J Am Soc Nephrol, Vol. 14, No. 5. (May 2003), pp. 1123-1131.

Advanced glycation end products (AGE) are filtered by glomeruli and reabsorbed and metabolized by proximal tubule cells (PTC). In renal failure, decreased renal AGE metabolism likely accounts for the accumulation in serum that is related to uremic complications. In diabetes, AGE generation is increased, and the handling mechanisms in PTC are likely associated with the pathogenesis of tubulointerstitial injury. It is therefore important to clarify the mechanisms of the AGE metabolism to develop a strategy for removing AGE in uremia and to elucidate the pathogenesis of diabetic nephropathy. To this end, this study focused on the molecular analysis of megalin, a multi-ligand endocytic receptor, in PTC. AGE uptake analysis was performed using the rat yolk sac-derived L2 cell line system established for the analysis of megalin's endocytic functions. The cells mediated specific internalization and degradation of AGE, which were significantly blocked by anti-megalin IgG, indicating that megalin is involved in the cellular processes. However, cell surface AGE-binding assays and ligand blot analysis revealed no evidence that megalin is a direct AGE receptor. Affinity chromatography and ligand blot analysis originally revealed that 200-kD and 400-kD proteins in the cells bind to AGE and the 200-kD protein to megalin in a Ca(2+)-dependent manner. The binding of megalin with the 200-kD protein was suppressed by receptor-associated protein (RAP), a ligand for megalin. In conclusion, megalin functions for endocytosis of AGE via an indirect mechanism. L2 cells express novel AGE-binding proteins, one of which may interact with megalin.

Significance of proximal tubular metabolism of advanced glycation end products in kidney diseases.

A Saito — 2008-01-14T11:55:52-00:00

Ann N Y Acad Sci, Vol. 1043 (June 2005), pp. 637-643.

Advanced glycation end products (AGEs) are formed by the nonenzymatic Maillard reaction between sugars and proteins. Low-molecular weight AGEs are filtered by renal glomeruli and then reabsorbed and metabolized by proximal tubule cells (PTCs). High-molecular weight AGEs are also delivered to PTCs in proteinuric states. In patients with diabetes, AGE generation is increased, and the actions of AGEs on PTCs are likely involved in the pathogenesis of diabetic nephropathy. In patients with chronic renal failure (CRF), reduced renal metabolism of AGEs likely accounts for the accumulation of AGEs in serum, leading to uremic complications including dialysis-related amyloidosis. AGE precursors such as reactive carbonyl compounds also accumulate in the sera of patients with CRF. It is likely that PTCs take up AGEs and AGE precursors via specific endocytotic receptors or transporters. Megalin is a multiligand endocytotic receptor that is abundantly expressed on PTCs. There is evidence that megalin is involved in the cellular uptake and degradation of AGEs. We previously reported a cell therapy model involving implantation of megalin-expressing cells into experimental mice with renal failure for elimination of uremic toxin proteins. Further studies are needed to clarify the molecular mechanisms of the metabolism of AGEs and their precursors to develop a strategy for the treatment of diabetic nephropathy and uremic complications of CRF.

Role of megalin, a proximal tubular endocytic receptor, in the pathogenesis of diabetic and metabolic syndrome-related nephropathies: protein metabolic overload hypothesis.

A Saito — 2008-01-13T08:13:07-00:00

Nephrology (Carlton), Vol. 10 Suppl (October 2005)

Megalin is an endocytic receptor on the apical membranes of proximal tubule cells (PTC) in the kidney, and is involved in the reabsorption and metabolism of various proteins that have been filtered by glomeruli. Patients with diabetes, especially type 2 diabetes, or metabolic syndrome are likely to have elevated serum levels of advanced glycation end products, liver-type fatty acid binding protein, angiotensin II, insulin and leptin, and renal metabolism of these proteins is potentially overloaded. Some of these proteins are themselves nephrotoxic, while others are carriers of nephrotoxic molecules. Megalin is involved in the proximal tubular uptake of these proteins. We hypothesize that megalin-mediated metabolic overload in PTC leads to compensatory cellular hypertrophy and sustained Na+ reabsorption, causing systemic hypertension and glomerular hyperfiltration via tubuloglomerular feedback, and named this as 'protein metabolic overload hypothesis'. Impaired metabolism of bioactive proteins such as angiotensin II and insulin in PTC may enhance hypertrophy of PTC and/or Na+ reabsorption. Sleep apnoea syndrome, a frequent complication of diabetes and metabolic syndrome, may cause renal hypoxia and result in relative overload of protein metabolism in the kidneys. The development of strategies to identify patients with diabetes or metabolic syndrome who are at high risk for renal metabolic overload would allow intensive treatment of these patients in an effort to prevent the development of nephropathy. Further studies on the intracellular molecular signalling associated with megalin-mediated metabolic pathways may lead to the development of novel strategies for the treatment of nephropathies related to diabetes and metabolic syndrome.

Construction of an open-access database that integrates cross-reference information from the transcriptome and proteome of immune cells.

A Hijikata — 2007-12-26T06:59:16-00:00

Bioinformatics, Vol. 23, No. 21. (1 November 2007), pp. 2934-2941.

MOTIVATION: Although a huge amount of mammalian genomic data does become publicly available, there are still hurdles for biologists to overcome before such data can be fully exploited. One of the challenges for gaining biological insight from genomic data has been the inability to cross-reference transcriptomic and proteomic data using a single informational platform. To address this, we constructed an open-access database that enabled us to cross-reference transcriptomic and proteomic data obtained from immune cells. RESULTS: The database, named RefDIC (Reference genomics Database of Immune Cells), currently contains: (i) quantitative mRNA profiles for human and mouse immune cells/tissues obtained using Affymetrix GeneChip technology; (ii) quantitative protein profiles for mouse immune cells obtained using two-dimensional gel electrophoresis (2-DE) followed by image analysis and mass spectrometry and (iii) various visualization tools to cross-reference the mRNA and protein profiles of immune cells. RefDIC is the first open-access database for immunogenomics and serves as an important information-sharing platform, enabling a focused genomic approach in immunology. AVAILABILITY: All raw data and information can be accessed from http://refdic.rcai.riken.jp/. The microarray data is also available at http://cibex.nig.ac.jp/ under CIBEX accession no. CBX19, and http://www.ebi.ac.uk/pride/ under PRIDE accession numbers 2354-2378 and 2414.

Regulation of the CAMP gene by 1,25(OH)2D3 in various tissues.

AF Gombart — 2007-12-21T03:37:43-00:00

J Steroid Biochem Mol Biol, Vol. 103, No. 3-5. (March 2007), pp. 552-557.

The induction of antimicrobial peptides such as the human cathelicidin, CAMP/hCAP18, by 1,25(OH)(2)D(3) provides a very exciting therapeutic approach in boosting immunity against infectious diseases. To explore the range of cell types and expand the number of cell models for studying the regulation of CAMP gene expression by 1,25(OH)(2)D(3), we treated cell lines from various tissue types and determined CAMP gene expression. Also, we tested additional compounds together with 1,25(OH)(2)D(3) to look for possible cooperative activation of the gene. We identified 1,25(OH)(2)D(3)-mediated induction of the CAMP gene in B-cell lymphomas, prostate and endometrial cancer lines and found cooperative activation with the histone deacetylase inhibitor sodium butyrate. The data suggest that regulation of CAMP by 1,25(OH)(2)D(3) is potentially important in a wide range of tissues.

Hypoxia promotes fibrogenesis in vivo via HIF-1 stimulation of epithelial-to-mesenchymal transition

Debra Higgins — 2007-12-07T09:40:17-00:00

J. Clin. Invest., Vol. 117, No. 12. (3 December 2007), pp. 3810-3820.

Hypoxia has been proposed as an important microenvironmental factor in the development of tissue fibrosis; however, the underlying mechanisms are not well defined. To examine the role of hypoxia-inducible factor1 (HIF-1), a key mediator of cellular adaptation to hypoxia, in the development of fibrosis in mice, we inactivated Hif-1alpha in primary renal epithelial cells and in proximal tubules of kidneys subjected to unilateral ureteral obstruction (UUO) using Cre-loxPmediated gene targeting. We found that Hif-1alpha enhanced epithelial-to-mesenchymal transition (EMT) in vitro and induced epithelial cell migration through upregulation of lysyl oxidase genes. Genetic ablation of epithelial Hif-1alpha inhibited the development of tubulointerstitial fibrosis in UUO kidneys, which was associated with decreased interstitial collagen deposition, decreased inflammatory cell infiltration, and a reduction in the number of fibroblast-specific protein1expressing (FSP-1expressing) interstitial cells. Furthermore, we demonstrate that increased renal HIF-1alpha expression is associated with tubulointerstitial injury in patients with chronic kidney disease. Thus, we provide clinical and genetic evidence that activation of HIF-1 signaling in renal epithelial cells is associated with the development of chronic renal disease and may promote fibrogenesis by increasing expression of extracellular matrixmodifying factors and lysyl oxidase genes and by facilitating EMT. 10.1172/JCI30487

Cyclosporin in idiopathic glomerular disease associated with the nephrotic syndrome : Workshop recommendations

DC Cattran — 2007-12-03T15:52:14-00:00

Kidney Int, Vol. 72, No. 12. (2007), pp. 1429-1447.

Diabetes, glycaemic control and mortality risk in patients on haemodialysis: the Japan Dialysis Outcomes and Practice Pattern Study

Hayashino — 2007-07-02T16:51:39-00:00

Diabetologia, Vol. 50, No. 6. (June 2007), pp. 1170-1177.

Association of solute carrier family 12 (sodium/chloride) member 3 with diabetic nephropathy, identified by genome-wide analyses of single nucleotide polymorphisms.

N Tanaka — 2007-11-06T04:23:45-00:00

Diabetes, Vol. 52, No. 11. (November 2003), pp. 2848-2853.

To identify genetic elements that might confer susceptibility to diabetic nephropathy, we performed a genome-wide analysis of gene-based single nucleotide polymorphisms (SNPs) in a large cohort of Japanese patients with diabetes. In case-control association studies, patients with type 2 diabetes were divided into two groups, one having retinopathy as well as overt nephropathy and the other (the control group) having diabetic retinopathy but with no signs of renal involvement. Genotyping of these patients at >55,000 SNP loci indicated a gene encoding solute carrier family 12 member 3 (SLC12A3) to be a good candidate for the susceptibility to diabetic nephropathy, in view of a significant association of one landmark SNP located in the 24th intron (chi(2) = 15.4, P = 0.000087, odds ratio = 2.53 [95% CI 1.57-4.09]). Subsequent analysis of additional genetic variations in this gene identified several SNPs that were significantly associated with nephropathy, especially one in exon 23 (+78 G to A: Arg913Gln, chi(2) = 18.5, P = 0.00002, odds ratio = 2.53 [95% CI 1.64-3.90]). The results implicated that substitution of Arg913 to Gln in the SLC12A3 gene might reduce the risk to develop diabetic nephropathy and suggested that the gene product might be a potential target for the prevention or treatment of this disease.

Cancer Epigenetics: Modifications, Screening, and Therapy.

Einav Nili Gal-Yam — 2007-10-30T03:51:01-00:00

Annu Rev Med (15 October 2007)

blacksquare, square, filled Abstract Deregulation of gene expression is a hallmark of cancer. Although genetic lesions have been the focus of cancer research for many years, it has become increasingly recognized that aberrant epigenetic modifications also play major roles in the tumorigenic process. These modifications are imposed on chromatin, do not change the nucleotide sequence of DNA, and are manifested by specific patterns of gene expression that are heritable through many cell divisions. We review these modifications in normal and cancer cells and the evolving approaches used to study them. Additionally, we outline advances in their potential use for cancer diagnostics and targeted epigenetic therapy. Expected final online publication date for the Annual Review of Medicine Volume 59 is January 7, 2008. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates.

Pitavastatin ameliorates albuminuria and renal mesangial expansion by downregulating NOX4 in db/db mice.

M Fujii — 2007-10-21T14:14:01-00:00

Kidney Int, Vol. 72, No. 4. (August 2007), pp. 473-480.

Recent studies have uncovered various pleiotrophic effects of 3-hydroxy-3-methylglutaryl coenzyme A reductase-inhibiting drugs (statins). Several studies have identified a beneficial effect of statins on diabetic nephropathy; however, the molecular mechanisms are unclear. In this study, we show that statin ameliorates nephropathy in db/db mice, a rodent model of type 2 diabetes, via downregulation of NAD(P)H oxidase NOX4, which is a major source of oxidative stress in the kidney. Pitavastatin treatment for 2 weeks starting at 12 weeks of age significantly reduced albuminuria in the db/db mice concomitant with a reduction of urinary 8-hydroxy-2'-deoxyguanosine and 8-epi-prostaglandin F(2alpha). Immunohistochemical analysis found increased amounts of 8-hydroxy-2'-deoxyguanosine and NOX4 protein in the kidney of db/db mice. Quantitative reverse transcription-polymerase chain reaction also showed increased levels of NOX4 mRNA. Pitavastatin normalized all of these changes in the kidneys of diabetic animals. Additionally, 12-week treatment with the statin completely normalized the levels of transforming growth factor-beta1 and fibronectin mRNA as well as the mesangial expansion characteristic of diabetic nephropathy. Our study demonstrates that pitavastatin ameliorates diabetic nephropathy in db/db mice by minimizing oxidative stress by downregulating NOX4 expression. These findings may provide insight into the mechanisms of statin therapy in early stages of diabetic nephropathy.

The relationships of proteinuria, serum creatinine, glomerular filtration rate with cardiovascular disease mortality in Japanese general population.

F Irie — 2007-10-02T03:05:30-00:00

Kidney Int, Vol. 69, No. 7. (April 2006), pp. 1264-1271.

Proteinuria, high serum creatinine, and reduced glomerular filtration rate (GFR) have been associated with increased mortality from cardiovascular disease (CVD) and all causes. However, the combined effect of proteinuria with serum creatinine and GFR on CVD or all-cause mortality has not been well investigated. We conducted a 10-year prospective cohort study of 30,764 men and 60,668 women aged 40-79 years who participated in annual health checkups in 1993. The Cox proportional hazards model was used to estimate the relative risk (RR) after adjusting for age, smoking, and other cardiovascular risk factors. The multivariable RR (95% confidence interval (CI)) of CVD death for positive vs negative proteinuria was 1.38 (1.05-1.79) among men and 2.15 (1.64-2.81) among women. The respective RR for the highest vs lowest creatinine groups (> or = 1.3 vs < or = 0.8 mg/dl for men and > or = 1.1 vs < or = 0.6 mg/dl for women) was 1.56 (1.19-2.04) among men and 2.15 (1.58-2.93) among women. The respective RR for GFR < 60 vs > r = 100 ml/min/1.73 m2 was 1.65 (1.25-2.18) among men and 1.81 (1.39-2.36) among women. For individuals with proteinuria combined by hypercreatininemia or reduced GFR, the risk of CVD death was two-fold higher in men and 4-6-fold higher in women compared to those without proteinuria and with normal creatinine level or GFR. Similar associations were observed for stroke, coronary heart disease, and all-cause mortality. Proteinuria, and hypercreatininemia or reduced GFR and their combination were significant predictors of CVD and all-cause mortality.

DNA damage-dependent cell cycle checkpoints and genomic stability.

K Ishikawa — 2007-06-18T11:11:31-00:00

DNA Cell Biol, Vol. 25, No. 7. (July 2006), pp. 406-411.

In response to genotoxic stress, which can be caused by environmental or endogenous genotoxic insults such as ionizing or ultraviolet radiation, various chemicals and reactive cellular metabolites, cell cycle checkpoints which slow down or arrest cell cycle progression can be activated, allowing the cell to repair or prevent the transmission of damaged or incompletely replicated chromosomes. Checkpoint machineries can also initiate pathways leading to apoptosis and the removal of a damaged cell from a tissue. The balance between cell cycle arrest and damage repair on one hand and the initiation of cell death, on the other hand, could determine if cellular or DNA damage is compatible with cell survival or requires cell elimination by apoptosis. Defects in these processes may lead to hypersensitivity to cellular stress, and susceptibility to DNA damage, genomic defects, and resistance to apoptosis, which characterize cancer cells. In this article, we have noted recent studies of DNA damage-dependent cell cycle checkpoints, which may be significant in preventing genomic instability.