Comparison of the effects of angiotensin-converting enzyme inhibition and angiotensin II receptor blockade on the evolution of spontaneous glomerular injury in male MWF/Ztm rats

Abstract

The mechanism by which angiotensin-converting enzyme (ACE) inhibitors prevent proteinuria and glomerulosclerosis in experimental nephropathies is not yet clear. Experimental evidence is available that the effect of ACE inhibitors on the glomerular function depends on the inhibition of angiotensin II generation, but it is possible that inhibition of the bradykinin breakdown also plays a relevant role. To establish the mediators of the effects of ACE inhibitors in glomerular injury, we compared the effects of the ACE inhibitor lisinopril with those of a specific angiotensin receptor (AT1) antagonist (ZD7155) on the renal function in male MWF/Ztm rats. After 4 months (end of the study), the untreated animals developed hypertension and proteinuria (160 +/- 10 mm Hg and 214 +/- 92 mg/24 h, respectively). In the lisinopril- and in the ZD7155-treated rats, a comparable systolic pressure control was achieved (121 +/- 12 and 118 +/- 14 mm Hg, respectively), and proteinuria was significantly prevented (averaging only 38 +/- 23 and 30 +/- 8 mg/24h, respectively) at the end of the study. The glomerular filtration rate was comparable in control and lisinopril-treated rats and significantly increased in ZD7155-treated rats. Both treatments significantly reduced the glomerular capillary pressure and significantly increased the ultrafiltration coefficient (Kf) as compared with untreated animals. In ZD7155-treated rats the Kf was also significantly higher than in untreated animals glomerular sclerosis and tubulointerstitital damage developed. Structural changes were absent in lisinopril- and ZD7155-treated animals. These results show that the antihypertensive and renal protective effects of ACE inhibitors are shared by the angiotensin receptor antagonist. Thus, angiotensin II is the likely mediator of proteinuria and glomerulosclerosis which develop spontaneously with age in this model.