Blocking angiotensin II ameliorates proteinuria and glomerular lesions in progressive mesangioproliferative glomerulonephritis

Background. The renin-angiotensin system is thought to be involved in the p rogression of glomerulonephritis (GN) into end-stage renal failure (ESRF) b ecause of the observed renoprotective effects of angiotensin-converting enz yme inhibitors (ACEIs). However, ACEIs have pharmacological effects other t han ACE inhibition that may help lower blood pressure and preserve glomerul ar structure. We previously reported a new animal model of progressive glom erulosclerosis induced by a single intravenous injection of an anti-Thy-1 m onoclonal antibody, MoAb 1-22-3, in uninephrectomized rats. Using this new model of progressive GN, we examined the hypothesis that ACEIs prevent the progression to ESRF by modulating the effects of angiotensin II (Ang II) on the production of transforming growth factor-beta (TGF-beta) and extracell ular matrix components. Methods. We studied the effect of an ACEI (cilazapril) and an Ang II type 1 receptor antagonist (candesartan) on the clinical features and morphologic al lesions in the rat model previously reported. After 10 weeks of treatmen t with equihypotensive doses of cilazapril, cilazapril plus Hoe 140 (a brad ykinin receptor B2 antagonist), candesartan, and hydralazine, we examined s ystolic blood pressure, urinary protein excretion, creatinine clearance, th e glomerulosclerosis index, and the tubulointerstitial lesion index. We per formed a semiquantitative evaluation of glomerular immunostaining for TGF-b eta and collagen types I and III by immunofluorescence study and of these c ortical mRNA levels by Northern blot analysis. Results. Untreated rats developed massive proteinuria, renal dysfunction, a nd severe glomerular and tubulointerstitial injury, whereas uninephrectomiz ed control rats did not. There was a significant increase in the levels of glomerular protein and cortical mRNA for TGF-beta and collagen types I and III in untreated rats. Cilazapril and candesartan prevented massive protein uria, increased creatinine clearance, and ameliorated glomerular and tubulo interstitial injury. These drugs also reduced levels of glomerular protein and cortical mRNA for TGF-beta and collagen types I and III. Hoe 140 failed to blunt the renoprotective effect of cilazapril. Hydralazine did not exhi bit a renoprotective effect. Conclusion. These results indicate that ACEIs prevent the progression to ES RF by modulating the effects of Ang II via Ang II type 1 receptor on the pr oduction of TGF-beta and collagen types I and III, as well as on intrarenal hemodynamics, but not by either increasing bradykinin activity or reducing blood pressure in this rat model of mesangial proliferative GN.