CiteULike: yavanna's library [139 articles]

Aliskiren, a novel renin inhibitor, is renoprotective in a model of advanced diabetic nephropathy in rats.

D Kelly — 2007-11-16T14:41:21-00:00

Diabetologia, Vol. 50, No. 11. (November 2007), pp. 2398-2404.

AIMS/HYPOTHESIS: Blockade of the renin-angiotensin system (RAS) with either ACE inhibitors or angiotensin receptor blocker is a key therapeutic strategy in slowing progression of diabetic nephropathy. Interruption of the RAS may also be achieved by blocking the activity of renin, the rate-limiting step in angiotensin II biosynthesis. However, it is not known whether drugs in this class also reduce the structural and functional manifestations of diabetic nephropathy. METHODS: Using diabetic transgenic (mRen-2)27 rats, a rodent model of advanced diabetic nephropathy, we compared the efficacy of the renin inhibitor, aliskiren (10 mg kg(-1) day(-1) by osmotic mini-pump), with the ACE inhibitor, perindopril (0.2 mg kg(-1) day(-1) in drinking water), over a 16 week period. RESULTS: Both perindopril and aliskiren reduced blood pressure, albuminuria and structural injury in experimental diabetic nephropathy, although not to the same extent. Aliskiren, at the dose used, did not reduce systemic blood pressure as much as perindopril, but both compounds were equally effective in reducing albuminuria and glomerulosclerosis in diabetic animals. The magnitude of interstitial fibrosis was attenuated to a greater degree by aliskiren than by perindopril. CONCLUSIONS/INTERPRETATION: These findings suggest that therapies aimed at different targets within the RAS may not have identical effects in attenuating structural injury in experimental diabetic nephropathy.

Control of [beta]-Catenin Phosphorylation/Degradation by a Dual-Kinase Mechanism

Chunming Liu — 2008-06-02T14:13:30-00:00

Cell, Vol. 108, No. 6. (22 March 2002), pp. 837-847.

Wnt regulation of [beta]-catenin degradation is essential for development and carcinogenesis. [beta]-catenin degradation is initiated upon amino-terminal serine/threonine phosphorylation, which is believed to be performed by glycogen synthase kinase-3 (GSK-3) in complex with tumor suppressor proteins Axin and adnomatous polyposis coli (APC). Here we describe another Axin-associated kinase, whose phosphorylation of [beta]-catenin precedes and is required for subsequent GSK-3 phosphorylation of [beta]-catenin. This "priming" kinase is casein kinase I[alpha] (CKI[alpha]). Depletion of CKI[alpha] inhibits [beta]-catenin phosphorylation and degradation and causes abnormal embryogenesis associated with excessive Wnt/[beta]-catenin signaling. Our study uncovers distinct roles and steps of [beta]-catenin phosphorylation, identifies CKI[alpha] as a component in Wnt/[beta]-catenin signaling, and has implications to pathogenesis/therapeutics of human cancers and diabetes.

Phosphorylation by p38 MAPK as an Alternative Pathway for GSK3beta Inactivation

Tina Thornton — 2008-05-02T15:08:25-00:00

Science, Vol. 320, No. 5876. (2 May 2008), pp. 667-670.

Glycogen synthase kinase 3 (GSK3) is involved in metabolism, neurodegeneration, and cancer. Inhibition of GSK3 activity is the primary mechanism that regulates this widely expressed active kinase. Although the protein kinase Akt inhibits GSK3 by phosphorylation at the N terminus, preventing Akt-mediated phosphorylation does not affect the cell-survival pathway activated through the GSK3 substrate -catenin. Here, we show that p38 mitogen-activated protein kinase (MAPK) also inactivates GSK3 by direct phosphorylation at its C terminus, and this inactivation can lead to an accumulation of -catenin. p38 MAPK-mediated phosphorylation of GSK3 occurs primarily in the brain and thymocytes. Activation of -catenin-mediated signaling through GSK3 inhibition provides a potential mechanism for p38 MAPK-mediated survival in specific tissues. 10.1126/science.1156037

Heme Oxygenase-1 Deficiency Promotes Epithelial-Mesenchymal Transition and Renal Fibrosis.

Jeong-Hae Kie — 2008-06-02T12:20:37-00:00

Journal of the American Society of Nephrology : JASN (21 May 2008)

Induction of heme oxygenase-1 (HO-1) is associated with potential antifibrogenic effects. The effects of HO-1 expression on epithelial-mesenchymal transition (EMT), which plays a critical role in the development of renal fibrosis, are unknown. In this study, HO-1(-/-) mice demonstrated significantly more fibrosis after 7 d of unilateral ureteral obstruction compared with wild-type mice, despite similar degrees of hydronephrosis. The obstructed kidneys of HO-1(-/-) mice also had greater macrophage infiltration and renal tubular TGF-beta1 expression than wild-type mice. In addition, the degree of EMT was more extensive in obstructed HO-1(-/-) kidneys, as assessed by alpha-smooth muscle actin and expression of S100A4 in proximal tubular epithelial cells. In vitro studies using proximal tubular cells isolated from HO-1(-/-) and wild-type kidneys confirmed these observations. In conclusion, HO-1 deficiency is associated with increased fibrosis, tubular TGF-beta1 expression, inflammation, and enhanced EMT in obstructive kidney disease. Modulation of the HO-1 pathway may provide a new therapeutic approach to progressive renal diseases.

Y-27632 prevents tubulointerstitial fibrosis in mouse kidneys with unilateral ureteral obstruction.

K Nagatoya — 2007-08-12T02:49:35-00:00

Kidney Int, Vol. 61, No. 5. (May 2002), pp. 1684-1695.

BACKGROUND: The small GTPase Rho is involved in cell-to-substratum adhesion and cell contraction. These actions of Rho mediated by downstream Rho effectors such as Rho-associated coiled-coil forming protein kinase (ROCK) may be partly responsible for the progression of renal interstitial fibrosis. METHODS: The anti-fibrosis effects of Y-27632, a specific ROCK inhibitor, were studied both in vivo (unilateral ureteral obstruction; UUO) and in vitro. To investigate the therapeutic efficacy of Y-27632 in UUO kidneys, smooth muscle alpha actin (SMalphaA) expression, macrophage infiltration and fibrosis in the obstructed kidneys were studied. SMalphaA, transforming growth factor beta (TGF-beta), alpha1 (I) collagen, osteopontin, macrophage chemoattractant peptide-1 (MCP-1), and intercellular adhesion molecule-1 (ICAM-1) gene expression were examined by Northern blotting. To elucidate the mechanism linking the Rho-ROCK pathway with renal fibrosis, the effects of Y-27632 on in vitro cell proliferation and cell migration were studied. RESULTS: In vivo analysis showed that Y-27632 suppressed SMalphaA expression, macrophage infiltration and interstitial fibrosis, and that Y-27632 suppressed SMalphaA, TGF-beta and alpha1 (I) collagen mRNA expression. In vitro analysis showed that Y-27632 did not suppress proliferation of renal fibroblasts but suppressed migration of macrophages. CONCLUSIONS: The Rho-ROCK system may play an important role in the development of tissue fibrosis, and the Rho-ROCK signaling pathway may be a new therapeutic target for preventing interstitial fibrosis in progressive renal disease.

The influence of glycogen synthase kinase 3 in limiting cell addition in the mammalian ear.

Zhenjie Lu — 2008-06-02T11:45:41-00:00

Developmental neurobiology (9 May 2008)

In the vestibular organs of the inner ear, an early postnatal decline in the capacity for cell proliferation appears to be responsible for limits to hair cell regeneration that are unique to mammals. We have investigated the time course of that decline in cell proliferation and its potential regulation by glycogen synthase kinase-3 (GSK3). Our immunoblots have revealed that inactive GSK3beta decreases postnatally in the murine utricular epithelium, as E-cadherin and the active forms of GSK3alpha and GSK3beta each increase. In cultured utricular epithelia, pharmacological inhibition of GSK3 by LiCl and SB-216763 increased cell proliferation across a range of postnatal ages. LiCl treatments also led to increased levels of beta-catenin and Snail and decreased expression of E-cadherin. Transfection with a dominant-negative GSK3beta enhanced proliferation in these epithelia in a cell-autonomous manner, while overexpression of wild-type GSK3beta markedly reduced it. The evidence from these measurements and experimental manipulations indicates that the balance of active and inactive forms of GSK3 helps to determine whether mammalian vestibular supporting cells will proliferate; permitting proliferation during early development when inactive GSK3 predominates and progressively inhibiting proliferation, and thereby limiting the capacity for hair cell regeneration as more GSK3 becomes active during the first week of postnatal maturation. (c) 2008 Wiley Periodicals, Inc. Develop Neurobiol, 2008.

Unraveling signalling cascades for the Snail family of transcription factors.

B De Craene — 2007-08-26T15:49:08-00:00

Cell Signal, Vol. 17, No. 5. (May 2005), pp. 535-547.

During development and carcinogenesis, the gradient of different molecular factors, the availability of corresponding receptors and the interplay between different signalling cascades combine to orchestrate the different stages. A good understanding of both developmental processes and oncogenesis leads to new insights into normal and aberrant regulation, processes that share some mutual key players. In this review, we will focus on the Snail family of transcription factors. These proteins, which share an evolutionarily conserved role in invertebrates and vertebrates, are implicated in several developmental processes, but are involved in carcinogenesis as well. We will highlight the different signalling cascades leading to the expression of Snail and Slug and how these factors are regulated on the transcriptional level. Then we will focus on how these factors execute their functions by repression of the numerous target genes that have been described to date.

Snail1 is involved in the renal epithelial-mesenchymal transition.

Jun Yoshino — 2007-08-29T05:10:00-00:00

Biochem Biophys Res Commun (3 August 2007)

The pathological significance of the tubular epithelial-mesenchymal transition (EMT) in kidney diseases is becoming increasingly recognized, and the transcription factor Snail1 plays a critical role in EMT. The results of this study show that Snail1 mRNA and protein were upregulated in the tubular epithelial cells of the obstructed kidneys in a rat model of unilateral ureteral obstruction and in human proximal tubule HKC-8 cells treated with TGF-beta1. Glycogen synthase kinase-3beta (GSK-3beta) regulates the Snail1 level by degrading Snail1 protein. The level of the phosphorylated inactive form of GSK-3beta was increased in the tubular epithelial cells of the obstructed kidney. TGF-beta1 increased the phosphorylated form of GSK-3beta in HKC-8 cells, and inhibition of GSK-3beta by the selective inhibitors lithium and TDZD-8 caused Snail1 protein to accumulate. This study demonstrated that Snail1 is involved in renal tubular EMT and that TGF-beta1 regulates Snail1 at the transcription and protein degradation levels.

Epithelial-to-Mesenchymal Transition Is a Potential Pathway Leading to Podocyte Dysfunction and Proteinuria

Yingjian Li — 2008-02-04T04:04:00-00:00

Am J Pathol, Vol. 172, No. 2. (1 February 2008), pp. 299-308.

Podocyte dysfunction plays an essential role in the pathogenesis of proteinuria and glomerulosclerosis. However, the mechanism underlying podocyte dysfunction in many common forms of chronic kidney diseases remains poorly understood. Here we tested the hypothesis that podocytes may undergo epithelial-to-mesenchymal transition after injury. Conditionally immortalized mouse podocytes were incubated with transforming growth factor (TGF)-1, a potent fibrogenic cytokine that is up-regulated in the diseased kidney. TGF-1 suppressed the slit diaphragm-associated protein P-cadherin, zonula occludens-1, and nephrin, a change consistent with loss of the epithelial feature. Meanwhile, TGF-1 induced the expression of the intermediate filament protein desmin and interstitial matrix components fibronectin and collagen I. Furthermore, TGF-1 promoted the expression and secretion of matrix metalloproteinase-9 by podocytes. Functionally, TGF-1 increased albumin permeability across podocyte monolayers, as demonstrated by a paracellular albumin influx assay. The expression of Snail, a key transcriptional factor that has been implicated in initiating epithelial-to-mesenchymal transition, was induced by TGF-1, and ectopic expression of Snail suppressed P-cadherin and nephrin in podocytes. In vivo, in addition to loss of nephrin and zonula occludens-1, mesenchymal markers such as desmin, fibroblast-specific protein-1, and matrix metalloproteinase-9 could be observed in glomerular podocytes of diabetic nephropathy. These results suggest that podocyte dedifferentiation and mesenchymal transition could be a potential pathway leading to their dysfunction, thereby playing a role in the genesis of proteinuria. 10.2353/ajpath.2008.070057

Apoptosis induced by endoplasmic reticulum stress involved in diabetic kidney disease

Guanghui Liu — 2008-05-29T14:46:18-00:00

Biochemical and Biophysical Research Communications, Vol. 370, No. 4. (13 June 2008), pp. 651-656.

Endoplasmic reticulum stress has been suggested to play a crucial role in the pathogenesis of diabetic complications. However, whether it is involved in the renal injury of diabetic nephropathy is still not known. We investigated the involvement of ER-associated apoptosis in kidney disease of streptozocin (STZ)-induced diabetic rats. We used albuminuria examination, hematoxylin & eosin (H&E) staining and TUNEL analysis to identify the existence of diabetic nephropathy and enhanced apoptosis. We performed immunohistochemistry, Western blot, and real-time PCR to analyze indicators of ER molecule chaperone and ER-associated apoptosis. GRP78, the ER chaperone, was up-regulated significantly in diabetic kidney compared to control. Furthermore, three hallmarks of ER-associated apoptosis, C/EBP homologous protein (CHOP), c-JUN NH2-terminal kinase (JNK) and caspase-12, were found to have activated in the diabetic kidney. Taken together, those results suggested that apoptosis induced by ER stress occurred in diabetic kidney, which may contribute to the development of diabetic nephropathy.

Antiproteinuric effect of the calcium channel blocker cilnidipine added to renin-angiotensin inhibition in hypertensive patients with chronic renal disease

T Fujita — 2007-12-03T15:50:27-00:00

Kidney Int, Vol. 72, No. 12. (17 October 2007), pp. 1543-1549.

"Black swan in the kidney": renal involvement in the antiphospholipid antibody syndrome.

CM Nzerue — 2006-12-11T05:43:48-00:00

Kidney Int, Vol. 62, No. 3. (September 2002), pp. 733-744.

The antiphosphospholipid antibody syndrome (APS) describes a clinical entity with recurrent thrombosis, fetal loss, thrombocytopenia in the presence of lupus anticoagulant and/or antibodies to cardiolipin. These antibodies may be associated with connective tissue diseases such as systemic lupus erythematosus (secondary APS) or be found in isolation (primary APS). Renal syndromes increasingly being reported in association with these antibodies include thrombotic microangiopathy, renal vein thrombosis, renal infarction, renal artery stenosis and/or malignant hypertension, increased allograft vascular thrombosis, and reduced survival of renal allografts. Although much has been understood concerning the biology of these antibodies and the pathogenesis of thrombosis, the optimal therapy remains to be elucidated. This article presents a historical review of the renal involvement in the antiphospholipid syndrome and discusses therapeutic options. Further research is needed.

Renal toxicity mediated by glucose degradation products in a rat model of advanced renal failure

Muller-Krebs — 2008-04-05T03:16:18-00:00

European Journal of Clinical Investigation, Vol. 38, No. 5. (May 2008), pp. 296-305.

Gain-of-function mutant of angiotensin II receptor, type 1A, causes hypertension and cardiovascular fibrosis in mice.

S Billet — 2008-05-01T13:03:36-00:00

The Journal of clinical investigation, Vol. 117, No. 7. (July 2007), pp. 1914-1925.

The role of the renin-angiotensin system has been investigated by overexpression or inactivation of its different genes in animals. However, there is no data concerning the effect of the constitutive activation of any component of the system. A knockin mouse model has been constructed with a gain-of-function mutant of the Ang II receptor, type 1A (AT(1A)), associating a constitutively activating mutation (N111S) with a C-terminal deletion, which impairs receptor internalization and desensitization. In vivo consequences of this mutant receptor expression in homozygous mice recapitulate its in vitro characteristics: the pressor response is more sensitive to Ang II and longer lasting. These mice present with a moderate (~20 mmHg) and stable increase in BP. They also develop early and progressive renal fibrosis and cardiac fibrosis and diastolic dysfunction. However, there was no overt cardiac hypertrophy. The hormonal parameters (low-renin and inappropriately normal aldosterone productions) mimic those of low-renin human hypertension. This new model reveals that a constitutive activation of AT(1A) leads to cardiac and renal fibrosis in spite of a modest effect on BP and will be useful for investigating the role of Ang II in target organs in a model similar to some forms of human hypertension.

Renoprotective role of the vitamin D receptor in diabetic nephropathy.

Z Zhang — 2007-10-21T13:55:28-00:00

Kidney Int (10 October 2007)

1,25-Dihydroxyvitamin D3 negatively regulates the renin-angiotensin system (RAS), which plays a critical role in the development of diabetic nephropathy. We tested if mice lacking the vitamin D receptor (VDR) are more susceptible to hyperglycemia-induced renal injury. Diabetic VDR knockout mice developed more severe albuminuria and glomerulosclerosis due to increased glomerular basement membrane thickening and podocyte effacement. More fibronectin (FN) and less nephrin were expressed in the VDR knockout mice compared to diabetic wild-type mice. In receptor knockout mice, increased renin, angiotensinogen, transforming growth factor-beta (TGF-beta), and connective tissue growth factor accompanied the more severe renal injury. 1,25-Dihydroxyvitmain D3 inhibited high glucose (HG)-induced FN production in cultured mesangial cells and increased nephrin expression in cultured podocytes. 1,25-Dihydroxyvitmain D3 also suppressed HG-induced activation of the RAS and TGF-beta in mesangial and juxtaglomerular cells. Our study suggests that receptor-mediated vitamin D actions are renoprotective in diabetic nephropathy.Kidney International advance online publication, 10 October 2007; doi:10.1038/sj.ki.5002572.

Obesity-Initiated Metabolic Syndrome and the Kidney: A Recipe for Chronic Kidney Disease?

Susan Bagby — 2008-05-01T12:45:20-00:00

J Am Soc Nephrol, Vol. 15, No. 11. (1 November 2004), pp. 2775-2791.

10.1097/01.ASN.0000141965.28037.EE

The Metabolic Syndrome as a Risk Factor for Chronic Kidney Disease: More than a Fat Chance?

Jeffrey Schelling — 2008-05-01T12:43:50-00:00

J Am Soc Nephrol, Vol. 15, No. 11. (1 November 2004), pp. 2773-2774.

10.1097/01.ASN.0000141964.68839.BB

The Relationship between Hyperinsulinemia, Hypertension and Progressive Renal Disease

Fadi El-Atat — 2008-05-01T12:41:27-00:00

J Am Soc Nephrol, Vol. 15, No. 11. (1 November 2004), pp. 2816-2827.

The incidence of end-stage renal disease (ESRD) has risen dramatically in the past decade, mainly due to the increasing prevalence of diabetes mellitus, and both impaired glucose tolerance and hypertension are important contributors to rising rates of ESRD. Obesity, especially the visceral type, is associated with peripheral resistance to insulin actions and hyperinsulinemia, which predisposes to development of diabetes. A common genetic predisposition to insulin resistance and hypertension and the coexistence of these two disorders predisposes to premature atherosclerosis. A constellation of metabolic and cardiovascular derangements, which also includes dyslipidemia, dysglycemia, endothelial dysfunction, fibrinolytic and inflammatory abnormalities, left ventricular hypertrophy, microalbuminuria, and increased oxidative stress, is referred to as the cardiometabolic syndrome. The components of this syndrome, individually and interdependently, substantially increase the risk of renal disease, cardiovascular disease (CVD) and mortality. Similar findings and cardiorenal risk factors can occur in subjects with android obesity without excess body weight. Recently, microalbuminuria has been gaining momentum as a component and marker for the cardiometabolic syndrome, in addition to being an early marker for progressive renal disease in patients with this syndrome or in those with diabetes. Furthermore, it is now established as an independent predictor of CVD and CVD mortality. This review examines the relationship between insulin resistance/hyperinsulinemia and hypertension in the context of cardiometabolic syndrome, progressive renal disease and accelerated CVD. The importance of microalbuminuria as an early marker for the cardiometabolic syndrome is also discussed in this review. 10.1097/01.ASN.0000133698.80390.37

AMP-activated protein kinase: the energy charge hypothesis revisited.

DG Hardie — 2008-04-28T07:21:47-00:00

BioEssays : news and reviews in molecular, cellular and developmental biology, Vol. 23, No. 12. (December 2001), pp. 1112-1119.

The AMP-activated protein kinase cascade is a sensor of cellular energy charge, and its existence provides strong support for the energy charge hypothesis first proposed by Daniel Atkinson in the 1960s. The system is activated in an ultrasensitive manner by cellular stresses that deplete ATP (and consequently elevate AMP), either by inhibiting ATP production (e.g., hypoxia), or by accelerating ATP consumption (e.g., exercise in muscle). Once activated, it switches on catabolic pathways, both acutely by phosphorylation of metabolic enzymes and chronically by effects on gene expression, and switches off many ATP-consuming processes. Recent work suggests that activation of AMPK is responsible for many of the effects of physical exercise, both the rapid metabolic effects and the adaptations that occur during training. Dominant mutations in regulatory subunit isoforms (gamma2 and gamma3) of AMPK, which appear to increase the basal activity in the absence of AMP, lead to hypertrophy of cardiac and skeletal muscle respectively.

A Transgenic Model of Visceral Obesity and the Metabolic Syndrome

Hiroaki Masuzaki — 2008-04-25T13:47:55-00:00

Science, Vol. 294, No. 5549. (7 December 2001), pp. 2166-2170.

10.1126/science.1066285

Reversal of Obesity- and Diet-Induced Insulin Resistance with Salicylates or Targeted Disruption of Ikkbeta

Minsheng Yuan — 2005-07-14T11:42:55-00:00

Science, Vol. 293, No. 5535. (31 August 2001), pp. 1673-1677.

Salicylate-induced proximal tubular dysfunction.

V Tsimihodimos — 2007-09-29T14:01:04-00:00

Am J Kidney Dis, Vol. 50, No. 3. (September 2007), pp. 463-467.

We describe the case of a 17-year-old girl who was admitted to our clinic for drug poisoning. Twelve hours after the ingestion of 25 tablets of aspirin (12.5 g of acetylsalicylic acid), the patient had a generalized proximal tubular dysfunction characterized by glucosuria (in the face of normal serum glucose levels), proteinuria, and uric acid wasting. Further characterization of the tubular dysfunction using high-resolution proton nuclear magnetic resonance spectroscopy of the urine showed a pattern consistent with proximal tubular injury. An important characteristic of the salicylate-induced proximal tubular dysfunction in our patient was its rapid reversibility. A trend toward normalization of fractional excretion values of electrolytes was observed 2 days after ingestion. Determination of serum and urine metabolites and spectroscopy of urine 15 days later showed no evidence of tubular dysfunction. The mechanisms potentially implicated in the pathogenesis of salicylate-induced Fanconi syndrome are discussed and a brief review of the relevant literature is provided.

Insulin resistance, inflammatory biomarkers, and adipokines in patients with chronic kidney disease: effects of angiotensin II blockade.

SG de Vinuesa — 2008-01-24T04:22:43-00:00

J Am Soc Nephrol, Vol. 17, No. 12 Suppl 3. (December 2006)

Patients with chronic kidney disease (CKD) present a high prevalence of insulin resistance (IR). Some studies suggest that angiotensin II may influence some cellular pathways that contribute to the pathogenesis of IR and stimulate the release of proinflammatory cytokines. Fifty-two patients who had stages 3 and 4 CKD and no diabetes were administered an angiotensin receptor blocker (ARB), olmesartan (40 mg), for 16 wk. Before and after ARB treatment, metabolic and inflammatory parameters and adipokines were measured. IR was calculated by Homeostasis Model Assessment (HOMA) index. Baseline data were compared with data that were obtained from 25 healthy control individuals of similar age and normal renal function. Compared with control subjects, patients with CKD presented significantly higher BP and waist circumference, higher triglycerides and lower HDL levels, higher insulin levels, and higher mean HOMA index (6.0 +/- 2.7 versus 2.9 +/- 2.2 muU/ml x mmol/L; P < 0.001). In addition, patients with CKD had increased levels of high-sensitivity C-reactive protein, TNF-alpha, and IL-6. In patients with CKD, leptin was positively correlated to abdominal obesity, insulin levels, and IL-6, and adiponectin was inversely correlated to abdominal obesity and insulin levels. Olmesartan treatment resulted in a significant decrease of BP, urinary protein excretion, plasma glucose (99 +/- 16 versus 92 +/- 14 mg/dl; P < 0.05), insulin (23.1 +/- 8.8 versus 19.9 +/- 9; P < 0.05), HOMA index (6.0 +/- 2.7 versus 4.7 +/- 2.8; P < 0.05), and glycated hemoglobin (5.33 +/- 0.58 versus 4.85 +/- 0.81%; P < 0.01). At the same time, there was a significant reduction of high-sensitivity C-reactive protein levels, from 4.45 mg/L (2.45 to 9.00) to 3.55 mg/L (1.80 to 5.40; P < 0.05) and fibrinogen (412 +/- 100 versus 370 +/- 105 mg/dl; P < 0.05). There were no significant differences in adipokine levels after olmesartan treatment. These data demonstrate that patients with CKD have a high prevalence of IR, metabolic syndrome, and chronic inflammation and that the administration of the ARB olmesartan improves IR and inflammation markers in these patients. Plasma adipokine levels that are related to several metabolic risk factors in patients with CKD were not modified by ARB therapy.

Metabolic Syndrome Is not a Risk Factor for Kidney Dysfunction in Obese Non-diabetic Subjects.

A Gatti — 2008-04-13T11:47:47-00:00

Obesity (Silver Spring, Md.), Vol. 16, No. 4. (April 2008), pp. 899-901.

Objective:To investigate whether insulin resistance (IR) and the metabolic syndrome (MS) are associated with kidney dysfunction in obese non-diabetic (OND) subjects.Methods and Procedures:Three-hundred and eighty (113M/267F; age = 41 +/- 14 years) OND subjects (BMI >/= 30 kg/m(2); range = 43 +/- 8 kg/m(2)) were studied. Anthropometric measures, blood pressure, fasting glucose, insulin, lipid profile, and serum creatinine were evaluated. Glomerular filtration rate (GFR) was estimated (e-GFR) with the Modification of Diet in Renal Disease equation. Chronic kidney disease (CKD) was defined as e-GFR <60 ml/min/1.73 m(2).Results:e-GFR was associated with gender (being lower in women) (P = 0.001) and age (P < 0.0001). CKD was present in 32 subjects (8.4%), who were older (P < 0.0001) and more frequently affected by hypertension (P = 0.04) as compared to subjects without CKD. MS was present in 212 (55.8%) subjects. They were older (P< 0.001), had lower e-GFR (P = 0.02) and were more frequently affected by CKD (odds ratio (OR), 95% confidence interval (CI) = 2.3, 1.1-5.1) than those without MS. However, differences in e-GFR values and in the risk of CKD were no longer statistically significant after adjusting for age (P = 0.99 for e-GFR and OR, 95% CI = 1.2, 0.5-2.8 for the risk of CKD, respectively). Homeostasis model assessment of IR (HOMA(IR)) index was neither higher in subject with CKD (P = 0.1) nor inversely correlated with e-GFR (r = 0.1, P = 0.1).Discussion:In OND individuals the risk of CKD is independent of the MS and related abnormalities. This suggests that these individuals are not susceptible to a further deleterious role on kidney function on the top of that played by obesity itself.Obesity (2008) 16 4, 899-901. doi:10.1038/oby.2007.59.

Achieving blood pressure targets during dialysis improves control but increases intradialytic hypotension.

A Davenport — 2008-04-14T22:34:37-00:00

Kidney international, Vol. 73, No. 6. (March 2008), pp. 759-764.

Cardiovascular disease remains the most common cause of mortality in patients with end-stage kidney disease treated by regular hemodialysis. To improve blood pressure control and reduce cardiovascular risk, the United Kingdom Renal Association standards committee introduced pre- and post-dialysis target blood pressures of less than 140/90 and 130/80 mm Hg, respectively. We audited blood pressure control and symptomatic intradialytic hypotension requiring fluid resuscitation in the Greater London area renal centers that serve 2630 patients. The study captured 7890 hemodialysis sessions during a 1-week period where only 36% of the patients achieved the pre-dialysis target and 42% the post-dialysis target, with a wide variation between centers. Different antihypertensive medication prescriptions did not affect achievement of these targets. Fifteen percent of the patients suffered symptomatic hypotension requiring fluid resuscitation associated with significantly greater interdialytic weight gains. Our study found that intradialytic hypotension was significantly greater in centers that achieved better post-dialysis blood pressure targeting.

Is there a need to optimize glycemic control in hemodialyzed diabetic patients?

B Feldt-Rasmussen — 2008-04-09T15:53:03-00:00

Kidney Int, Vol. 70, No. 8. (0000), pp. 1392-1394.

Prognosis and risk factors for idiopathic membranous nephropathy with nephrotic syndrome in Japan

Hideo Shiiki — 2008-04-04T12:12:24-00:00

Kidney Int, Vol. 65, No. 4. (April 2004), pp. 1400-1407.

Pathologic findings of initial biopsies reflect the outcomes of membranous nephropathy

Keiichi Yoshimoto — 2008-04-04T12:10:33-00:00

Kidney Int, Vol. 65, No. 1. (January 2004), pp. 148-153.

Intravenous immunoglobulin (IVIg) therapy in MPO-ANCA related polyangiitis with rapidly progressive glomerulonephritis in Japan.

E Muso — 2005-01-20T00:29:54-00:00

Jpn J Infect Dis, Vol. 57, No. 5. (October 2004), pp. 17-18.

Intravenous immunoglobulins for relapses of systemic vasculitides associated with antineutrophil cytoplasmic autoantibodies: Results of a multicenter, prospective, open-label study of twenty-two patients

Valérie Martinez — 2008-04-03T13:20:30-00:00

Arthritis & Rheumatism, Vol. 58, No. 1. (2008), pp. 308-317.

To evaluate at 9 months and 24 months the safety and efficacy of intravenous immunoglobulins (IVIGs) administered for 6 months to treat relapses of Wegener's granulomatosis (WG) or microscopic polyangiitis (MPA) occurring either under treatment or during the year following discontinuation of corticosteroids and/or immunosuppressants.Patients received IVIGs (0.5 gm/kg/day for 4 days) as additional therapy administered monthly for 6 months and were assessed every 3-6 months. Corticosteroids could be maintained or reintroduced at the time of relapse; immunosuppressants could be continued but could not be reintroduced. At months 9 (end point) and 24 (followup), the following information was collected: complete or partial remission, relapse as assessed with the Birmingham Vasculitis Activity Score (BVAS) 2005, and tolerance and safety of IVIG therapy.Twenty-two Caucasian patients (7 men and 15 women) were studied: 19 had WG, and 3 had MPA. Their median age was 53 years (range 19-75 years), and their median duration of systemic vasculitis was 27 months (range 7-109 months). Their median BVAS 2005 score was 11 (range 3-25). At study entry, 21 patients were ANCA positive, and 21 patients were taking steroids and/or immunosuppressants. All patients experiencing relapse were treated with the same drug(s) plus IVIGs. All patients initially responded to IVIG therapy. By month 9, 13 patients had complete remission, 1 had partial remission, 7 had relapse, and 1 had treatment failure. In 8 of the 14 patients who had remission, the response persisted at month 24. Seven patients experienced minor side effects.IVIGs induced complete remissions of relapsed ANCA-associated vasculitides in 13 of 22 patients at month 9. Because of the good safety and tolerance profiles of IVIGs, these agents can be included in a therapeutic strategy with other drugs used to treat relapses of WG or MPA.

Microscopic polyangiitis with ocular manifestations as the initial presenting sign.

A Hara — 2008-04-02T13:10:41-00:00

The American journal of the medical sciences, Vol. 334, No. 4. (October 2007), pp. 308-310.

Microscopic polyangiitis (MPA) rarely affects ocular small vessels, in contrast to the pulmonary and/or renal vasculature of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. This report focuses on a 60-year-old woman who had MPA with ocular manifestations as the initial clinical symptom, which were improved by steroid administration. This case report provides an insight for early diagnosis of eye lesions in patients with MPA to prevent the development of both ocular and life-threatening organ damage.

Dermatological manifestations associated with microscopic polyangiitis.

S Niiyama — 2008-04-02T13:09:41-00:00

Rheumatology international, Vol. 28, No. 6. (April 2008), pp. 593-595.

Microscopic polyangiitis (MPA) is a systemic small vessel vasculitis, which, although primarily associated with necrotizing and crescentic glomerulonephritis and pulmonary capillaritis, often has cutaneous and musculoskeltal features. Although the skin is affected in 20-70% of patients, the precise description has been limited. This retrospective study analyzed clinical manifestations in patients of MPA with skin eruptions.

A novel subtype of type 1 diabetes mellitus characterized by a rapid onset and an absence of diabetes-related antibodies. Osaka IDDM Study Group.

A Imagawa — 2008-04-01T13:08:50-00:00

N Engl J Med, Vol. 342, No. 5. (3 February 2000), pp. 301-307.

BACKGROUND AND METHODS: Type 1 diabetes mellitus is now classified as autoimmune (type 1A) or idiopathic (type 1B), but little is known about the latter. We classified 56 consecutive Japanese adults with type 1 diabetes according to the presence or absence of glutamic acid decarboxylase antibodies (their presence is a marker of autoimmunity) and compared their clinical, serologic, and pathological characteristics. RESULTS: We divided the patients into three groups: 36 patients with positive tests for serum glutamic acid decarboxylase autoantibodies, 9 with negative tests for serum glutamic acid decarboxylase antibodies and glycosylated hemoglobin values higher than 11.5 percent, and 11 with negative tests for serum glutamic acid decarboxylase antibodies and glycosylated hemoglobin values lower than 8.5 percent. In comparison with the first two groups, the third group had a shorter mean duration of symptoms of hyperglycemia (4.0 days), a higher mean plasma glucose concentration (773 mg per deciliter [43 mmol per liter]) in spite of lower glycosylated hemoglobin values, diminished urinary excretion of C peptide, a more severe metabolic disorder (with ketoacidosis), higher serum pancreatic enzyme concentrations, and an absence of islet-cell, IA-2, and insulin antibodies. Immunohistologic studies of pancreatic-biopsy specimens from three patients with negative tests for glutamic acid decarboxylase autoantibodies and low glycosylated hemoglobin values revealed T-lymphocyte-predominant infiltrates in the exocrine pancreas but no insulitis and no evidence of acute or chronic pancreatitis. CONCLUSIONS: Some patients with idiopathic type 1 diabetes have a nonautoimmune, fulminant disorder characterized by the absence of insulitis and of diabetes-related antibodies, a remarkably abrupt onset, and high serum pancreatic enzyme concentrations.

Rituximab treatment of idiopathic membranous nephropathy.

FC Fervenza — 2008-03-31T12:48:55-00:00

Kidney Int, Vol. 73, No. 1. (January 2008), pp. 117-125.

Idiopathic membranous nephropathy is a common cause of nephrotic syndrome whose pathogenesis may involve B-cell functions. Rituximab is a monoclonal antibody that binds to the CD20 antigen on B cells thereby deleting them. We conducted an open-label pilot trial of rituximab treatment in 15 severely nephrotic patients with proteinuria refractory to angiotensin-converting enzyme inhibition and/or receptor blockade but with adequately controlled blood pressure. Rituximab was given 2 weeks apart and, at 6 months, patients who remained proteinuric but had recovered B-cell counts were given a second course of treatment. Proteinuria was significantly decreased by about half at 12 months. Of the 14 patients who completed follow-up, full remission was achieved in two and partial remission in six patients based upon the degree of proteinuria. Side effects were minor; however, we found no relationship between the response and number of B cells in the blood, CD20 cells in the kidney biopsy, degree of tubulointerstitial fibrosis, starting proteinuria or creatinine values. Rituximab appears effective in reducing proteinuria in some patients with idiopathic membranous nephropathy but prospective identification of responsive patients was not possible.

The short- and long-term outcomes of membranous nephropathy treated with intravenous immune globulin therapy. Kanazawa Study Group for Renal Diseases and Hypertension.

H Yokoyama — 2008-03-31T12:46:43-00:00

Nephrol Dial Transplant, Vol. 14, No. 10. (October 1999), pp. 2379-2386.

BACKGROUND: A considerable diversity in prognosis is seen with membranous nephropathy (MN). A recent report showed beneficial effects of immune globulin (Glb) therapy in Heymann nephritis, a rat model of MN. However, the early and late clinical effects of Glb in human MN have remained unclear. METHODS: We studied retrospectively 86 patients with primary MN from 1965 to 1988 who were followed for at least 5 years, or until renal or actual death. Thirty patients were non-randomly treated with 1-3 courses of intravenous immune globulin, 5-10 g/day (100-150 mg/kg/day) for 6 consecutive days. Based on electron microscopic (EM) findings, the patients were divided into two subtypes, i.e. homogeneous type with synchronous electron-dense deposits, and heterogeneous type with various stages of dense deposits, due to their different clinical outcomes. RESULTS: There was no difference in the initial clinicopathological states between Glb (n = 30) and non-Glb group (n = 56) (70 vs. 68% in nephrotic state; 37 vs. 39% in female, 50 vs. 52% in homogeneous type, 50 vs. 48% in heterogeneous type respectively). For the homogeneous type, at 6 months post-treatment, Glb therapy had induced earlier remission as compared to non-Glb treatments with corticosteroid alone or together with cyclophosphamide (57 vs. 10% respectively, P = 0.006). However, there was no significant difference in the early therapeutic effect for the heterogeneous type (13% for Glb vs. 5% for non-Glb in remission after 6 months), or in the final outcome for all groups (18% for Glb vs. 10% for non-Glb in renal death after 15 years). No adverse effects were recorded during or after Glb therapy. CONCLUSIONS: Our results suggest that short-term relatively low-dose intravenous Glb therapy has a beneficial effect in the earlier induction of remission in a subgroup of MN, the homogeneous type with EM findings of synchronous electron-dense deposits, but does not alter the long-term outcome of human MN.

Membranous nephropathy.

C Ponticelli — 2008-03-31T12:43:56-00:00

J Nephrol, Vol. 20, No. 3. (n 2007), pp. 268-287.

Membranous nephropathy (MN) is a glomerular disease characterized by proteinuria, usually in a nephrotic range, and variable natural course. The etiology is unknown in many cases, while in some patients, MN may be secondary to infection, to other diseases, or to exposure to drugs and toxic substances. In idiopathic MN, the antigens are probably located at the base of podocytes, and the glomerular lesions occur by the local formation of immune complexes, with consequent activation of complement and inflammation triggered by the membrane attack complex C5b-9. Patients with severe proteinuria, those with advanced tubulointerstitial changes at renal biopsy and those with increased serum creatinine at presentation have a poorer prognosis, while patients showing complete or even partial remission of proteinuria have a favorable prognosis. The indications for and types of treatment are controversial. There is no good evidence in favor of therapies based on corticosteroids alone. Cyclophosphamide and chlorambucil may increase the probability of remission, but the prolonged use of these agents may cause disquieting adverse effects. Good results have been obtained by alternating corticosteroids and a cytotoxic agent every other month for 6 months. Other potential treatments are represented by cyclosporine, synthetic adrenocorticotropic hormone (ACTH), mycophenolate mofetil, rituximab and intravenous immunoglobulins. Further studies addressed to recognizing the responsible antigen(s), and interventions directed to interfere with the specific antibodies, with regulators of glomerular permeability, and/or with factors regulating the complement activity might allow us to better understand the physiopathology of MN and to organize more specific and effective treatments in the near future.

Rosuvastatin-Induced Arrest in Progression of Renal Disease

DG Vidt — 2008-02-20T01:19:33-00:00

Cardiology, Vol. 102 (2004), pp. 52-60.

Endocrine regulation of energy metabolism by the skeleton.

NK Lee — 2008-02-15T00:11:05-00:00

Cell, Vol. 130, No. 3. (10 August 2007), pp. 456-469.

The regulation of bone remodeling by an adipocyte-derived hormone implies that bone may exert a feedback control of energy homeostasis. To test this hypothesis we looked for genes expressed in osteoblasts, encoding signaling molecules and affecting energy metabolism. We show here that mice lacking the protein tyrosine phosphatase OST-PTP are hypoglycemic and are protected from obesity and glucose intolerance because of an increase in beta-cell proliferation, insulin secretion, and insulin sensitivity. In contrast, mice lacking the osteoblast-secreted molecule osteocalcin display decreased beta-cell proliferation, glucose intolerance, and insulin resistance. Removing one Osteocalcin allele from OST-PTP-deficient mice corrects their metabolic phenotype. Ex vivo, osteocalcin can stimulate CyclinD1 and Insulin expression in beta-cells and Adiponectin, an insulin-sensitizing adipokine, in adipocytes; in vivo osteocalcin can improve glucose tolerance. By revealing that the skeleton exerts an endocrine regulation of sugar homeostasis this study expands the biological importance of this organ and our understanding of energy metabolism.

Visualizing Spatiotemporal Dynamics of Multicellular Cell-Cycle Progression

Asako Sakaue-Sawano — 2008-02-08T16:32:00-00:00

Cell, Vol. 132, No. 3. (8 February 2008), pp. 487-498.

Summary The cell-cycle transition from G1 to S phase has been difficult to visualize. We have harnessed antiphase oscillating proteins that mark cell-cycle transitions in order to develop genetically encoded fluorescent probes for this purpose. These probes effectively label individual G1 phase nuclei red and those in S/G2/M phases green. We were able to generate cultured cells and transgenic mice constitutively expressing the cell-cycle probes, in which every cell nucleus exhibits either red or green fluorescence. We performed time-lapse imaging to explore the spatiotemporal patterns of cell-cycle dynamics during the epithelial-mesenchymal transition of cultured cells, the migration and differentiation of neural progenitors in brain slices, and the development of tumors across blood vessels in live mice. These mice and cell lines will serve as model systems permitting unprecedented spatial and temporal resolution to help us better understand how the cell cycle is coordinated with various biological events.

Molecular biology: The expanding world of small RNAs

Helge Groszhans — 2008-01-27T13:19:05-00:00

Nature, Vol. 451, No. 7177. (24 January 2008), pp. 414-416.

Mast cell renin and a local renin-angiotensin system in the airway: Role in bronchoconstriction

Arul Veerappan — 2008-01-29T22:33:57-00:00

Proceedings of the National Academy of Sciences, Vol. 105, No. 4. (29 January 2008), pp. 1315-1320.

We previously reported that mast cells express renin, the rate-limiting enzyme in the reninangiotensin cascade. We have now assessed whether mast cell renin release triggers angiotensin formation in the airway. In isolated rat bronchial rings, mast cell degranulation released enzyme with angiotensin I-forming activity blocked by the selective renin inhibitor BILA2157. Local generation of angiotensin (ANG II) from mast cell renin elicited bronchial smooth muscle contraction mediated by ANG II type 1 receptors (AT1R). In a guinea pig model of immediate type hypersensitivity, anaphylactic mast cell degranulation in bronchial rings resulted in ANG II-mediated constriction. As in rat bronchial rings, bronchoconstriction (BC) was inhibited by a renin inhibitor, an AT1R blocker, and a mast cell stabilizer. Anaphylactic release of renin, histamine, and -hexosaminidase from mast cells was confirmed in the effluent from isolated, perfused guinea pig lung. To relate the significance of this finding to humans, mast cells were isolated from macroscopically normal human lung waste tissue specimens. Sequence analysis of human lung mast cell RNA showed 100% homology between human lung mast cell renin and kidney renin between exons 1 and 10. Furthermore, the renin protein expressed in lung mast cells was enzymatically active. Our results demonstrate the existence of an airway reninangiotensin system triggered by release of mast-cell renin. The data show that locally produced ANG II is a critical factor governing BC, opening the possibility for novel therapeutic targets in the management of airway disease. 10.1073/pnas.0709739105

Identification of RPS14 as a 5q- syndrome gene by RNA interference screen

Benjamin Ebert — 2008-01-17T18:11:36-00:00

Nature, Vol. 451, No. 7176., pp. 335-339.

High field gradient targeting of magnetic nanoparticle-loaded endothelial cells to the surfaces of steel stents

Boris Polyak — 2008-01-15T22:39:52-00:00

Proceedings of the National Academy of Sciences, Vol. 105, No. 2. (15 January 2008), pp. 698-703.

A cell delivery strategy was investigated that was hypothesized to enable magnetic targeting of endothelial cells to the steel surfaces of intraarterial stents because of the following mechanisms: (i) preloading cells with biodegradable polymeric superparamagnetic nanoparticles (MNPs), thereby rendering the cells magnetically responsive; and (ii) the induction of both magnetic field gradients around the wires of a steel stent and magnetic moments within MNPs because of a uniform external magnetic field, thereby targeting MNP-laden cells to the stent wires. In vitro studies demonstrated that MNP-loaded bovine aortic endothelial cells (BAECs) could be magnetically targeted to steel stent wires. In vivo MNP-loaded BAECs transduced with adenoviruses expressing luciferase (Luc) were targeted to stents deployed in rat carotid arteries in the presence of a uniform magnetic field with significantly greater Luc expression, detected by in vivo optical imaging, than nonmagnetic controls. 10.1073/pnas.0708338105

Bone marrow stem cells contribute to repair of the ischemically injured renal tubule.

S Kale — 2007-10-02T04:46:22-00:00

J Clin Invest, Vol. 112, No. 1. (July 2003), pp. 42-49.

The paradigm for recovery of the renal tubule from acute tubular necrosis is that surviving cells from the areas bordering the injury must migrate into the regions of tubular denudation and proliferate to re-establish the normal tubular epithelium. However, therapies aimed at stimulating these events have failed to alter the course of acute renal failure in human trials. In the present study, we demonstrate that Lin-Sca-1+ cells from the adult mouse bone marrow are mobilized into the circulation by transient renal ischemia and home specifically to injured regions of the renal tubule. There they differentiate into renal tubular epithelial cells and appear to constitute the majority of the cells present in the previously necrotic tubules. Loss of stem cells following bone marrow ablation results in a greater rise in blood urea nitrogen after renal ischemia, while stem cell infusion after bone marrow ablation reverses this effect. Thus, therapies aimed at enhancing the mobilization, propagation, and/or delivery of bone marrow stem cells to the kidney hold potential as entirely new approaches for the treatment of acute tubular necrosis.

Renal SDF-1 signals mobilization and homing of CXCR4-positive cells to the kidney after ischemic injury

Florian Togel — 2005-04-09T16:26:31-00:00

Kidney International, Vol. 67, No. 5. (May 2005), pp. 1772-1784.

Early steroid treatment improves the recovery of renal function in patients with drug-induced acute interstitial nephritis

2008-01-11T03:30:40-00:00

Kidney International (9 January 2008)

Diffuse vascular calcification in a dialysis patient

2008-01-11T03:28:37-00:00

Kidney International (9 January 2008)

K/DOQI-recommended intact PTH levels do not prevent low-turnover bone disease in hemodialysis patients

2008-01-11T03:25:21-00:00

Kidney International (9 January 2008)

Acute chorea and bilateral basal ganglia lesions in a hemodialysis patient

K Kiryluk — 2008-01-11T03:23:21-00:00

Kidney International (9 January 2008)

Salt abuse: the path to hypertension

Wilhelm Schoner — 2008-01-08T01:11:41-00:00

Nat Med, Vol. 14, No. 1. (January 2008), pp. 16-17.