Low-dose mTOR inhibition by rapamycin attenuates progression in anti-thy1-induced chronic glomerulosclerosis of the rat.

@article{citeulike:2233529, abstract = {Treatment options in human mesangioproliferative glomerulonephritis/-scleroris, mostly IgA nephropathy, are limited. Progressive mesangioproliferative nephropathy represents a major cause of end-stage kidney disease. The present study explores the efficacy of low dose mTOR inhibiton by rapamycin in a chronic-progressive model of mesangioproliferative glomerulosclerosis (cGS). cGS was induced by high dose anti-thy1 antibody injection into uni-nephrectomized rats. Rapamycin administration (2.5 mg/kg/BW) was started 10 days after antibody injection and continued until week 20. cGS was characterized by advancing proteinuria, increased blood pressure, marked tubulointerstitial and glomerular fibrosis, cell proliferation and round cell infiltration, and impaired renal function. The course of chronic anti-thy1-induced glomerulosclerosis was significantly attenuated by low dose rapamycin treatment. In week 20, this was demonstrated by improvements in proteinuria (-38\%), systolic blood pressure (-17 mmHG), tubulointerstitial and glomerular histological matrix accumulation (-61\% and -24\%), TGF-beta1 overexpression (-41\% and -47\%), collagen I deposition (-53\% and -65\%), cell proliferation (-90\% and -76\%) and leukocyte number (macrophages -52\% and -53\%, lymphocytes -51\% and 58\%), respectively. Rapamycin improved renal function as well (blood creatinine -0.68 mg/dL, urea -66.7 mg/dL and creatinine clearance +0.13 ml/min/100 g BW). In conclusion, low-dose mTOR inhibition by rapamycin limits the progressive course of anti-thy1-induced renal disease towards chronic glomerulosclerosis, tubulointerstitial fibrosis and renal insufficiency. Renoprotection by rapamycin involved significant beneficial effects on multiple key pathways in the progression of chronic renal disease, i.e. proteinuria, extracellular matrix accumulation, renal cell proliferation and inflammatory cell infiltration. Key words: mTOR inhibition, rapamycin, mesangioprolifertive nephropathy, renal progression.}, address = {Nephrology, Charite, Humboldt University, Berlin, Germany.}, author = {Kraemer, Stephanie and Wang-Rosenke, Yingrui and Scholl, Valeska and Binder, Eva and Loof, Tanja and Khadzhynov, Dmytro and Kawachi, Hiroshi and Shimizu, Fujio and Diekmann, Fritz and Budde, Klemens and Neumayer, Hans Hellmut H. and Peters, Harm }, citeulike-article-id = {2233529}, doi = {10.1152/ajprenal.00379.2007}, issn = {0363-6127}, journal = {Am J Physiol Renal Physiol}, keywords = {gn, tor}, month = {December}, posted-at = {2008-01-15 04:54:40}, priority = {2}, title = {Low-dose mTOR inhibition by rapamycin attenuates progression in anti-thy1-induced chronic glomerulosclerosis of the rat.}, url = {http://dx.doi.org/10.1152/ajprenal.00379.2007}, year = {2007} }

TY - JOUR ID - citeulike:2233529 L3 - citeulike-article-id:2233529 TI - Low-dose mTOR inhibition by rapamycin attenuates progression in anti-thy1-induced chronic glomerulosclerosis of the rat. JF - Am J Physiol Renal Physiol AD - Nephrology, Charite, Humboldt University, Berlin, Germany. SN - 0363-6127 N2 - Treatment options in human mesangioproliferative glomerulonephritis/-scleroris, mostly IgA nephropathy, are limited. Progressive mesangioproliferative nephropathy represents a major cause of end-stage kidney disease. The present study explores the efficacy of low dose mTOR inhibiton by rapamycin in a chronic-progressive model of mesangioproliferative glomerulosclerosis (cGS). cGS was induced by high dose anti-thy1 antibody injection into uni-nephrectomized rats. Rapamycin administration (2.5 mg/kg/BW) was started 10 days after antibody injection and continued until week 20. cGS was characterized by advancing proteinuria, increased blood pressure, marked tubulointerstitial and glomerular fibrosis, cell proliferation and round cell infiltration, and impaired renal function. The course of chronic anti-thy1-induced glomerulosclerosis was significantly attenuated by low dose rapamycin treatment. In week 20, this was demonstrated by improvements in proteinuria (-38%), systolic blood pressure (-17 mmHG), tubulointerstitial and glomerular histological matrix accumulation (-61% and -24%), TGF-beta1 overexpression (-41% and -47%), collagen I deposition (-53% and -65%), cell proliferation (-90% and -76%) and leukocyte number (macrophages -52% and -53%, lymphocytes -51% and 58%), respectively. Rapamycin improved renal function as well (blood creatinine -0.68 mg/dL, urea -66.7 mg/dL and creatinine clearance +0.13 ml/min/100 g BW). In conclusion, low-dose mTOR inhibition by rapamycin limits the progressive course of anti-thy1-induced renal disease towards chronic glomerulosclerosis, tubulointerstitial fibrosis and renal insufficiency. Renoprotection by rapamycin involved significant beneficial effects on multiple key pathways in the progression of chronic renal disease, i.e. proteinuria, extracellular matrix accumulation, renal cell proliferation and inflammatory cell infiltration. Key words: mTOR inhibition, rapamycin, mesangioprolifertive nephropathy, renal progression. KW - gn KW - tor AU - Kraemer, Stephanie AU - Wang-Rosenke, Yingrui AU - Scholl, Valeska AU - Binder, Eva AU - Loof, Tanja AU - Khadzhynov, Dmytro AU - Kawachi, Hiroshi AU - Shimizu, Fujio AU - Diekmann, Fritz AU - Budde, Klemens AU - Neumayer, Hans Hellmut AU - Peters, Harm PY - 2007/12/19/ UR - http://dx.doi.org/10.1152/ajprenal.00379.2007 ER -