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.