Glomerular and tubulointerstitial soluble guanylate cyclase activity are discordantly altered in anti-thy1-induced chronic glomerulosclerosis. Stimulation of soluble guanylate cyclase signaling by Bay 41-2272 limits the progressive course of this model toward tubulointerstitial fibrosis and impaired renal function at least in part in a blood pressure-independent manner. The results suggest that soluble guanylate cyclase activation counteracts fibrosis and progression in chronic renal disease.

-dose mTOR inhibition by rapamycin attenuates progression in anti-thy1-induced chronic glomerulosclerosis of the rat. Am J Physiol Renal Physiol 294: F440-F449, 2008. First published December 19, 2007 doi:10.1152/ajprenal.00379.2007.-Treatment options in human mesangioproliferative glomerulonephritis/sclerosis, 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 inhibition by rapamycin in a chronic-progressive model of mesangioproliferative glomerulosclerosis (cGS). cGS was induced by high-dose anti-thy1 antibody injection into uninephrectomized rats. Rapamycin administration (2.5 mg ⅐ kg Ϫ1 ⅐ body wt Ϫ1 ) 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. KruskalWallis and Mann-Whitney U-tests were used for statistical analysis. 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 (Ϫ38%), systolic blood pressure (Ϫ16 mmHg), tubulointerstitial and glomerular histological matrix accumulation (Ϫ61 and Ϫ24%), transforming growth factor-␤1 overexpression (Ϫ41 and Ϫ47%), collagen I deposition (Ϫ53 and Ϫ65%), cell proliferation (Ϫ90 and Ϫ76%), and leukocyte number (macrophages Ϫ52 and Ϫ53%; lymphocytes Ϫ58 and 51%), respectively. Rapamycin improved renal function as well (blood creatinine Ϫ0.68 mg/dl, urea Ϫ66.7 mg/day, and creatinine clearance ϩ0.13 ml ⅐ min Ϫ1

Glomerular nitric oxide signaling via cGMP is markedly impaired during injury of anti-thy1 glomerulonephritis, while it is highly up-regulated during subsequent repair. Further pharmacologic soluble guanylate cyclase stimulation limits glomerular TGF-beta overexpression and matrix expansion, suggesting that the soluble guanylate cyclase enzyme represents an important antifibrotic pathway in glomerular disease.