Effects of different antihypertensive treatments on morphologic progression of diabetic nephropathy in uninephrectomized dogs

Abstract

We previously reported the renal hemodynamic effects of different antihypertensive regimens in uninephrectomized, alloxan-induced, diabetic (DM) beagle dogs following one year of treatment. Dogs were prospectively randomized to one of five groups (N = 26): nondiabetic controls, Group I; dogs with DM on no antihypertensive drugs, Group II; dogs on a converting enzyme inhibitor, lisinopril (L), Group III; dogs on a calcium antagonist, TA3090 (diltiazem-like), Group IV; and dogs on a combination of each drug, in reduced doses, Group V. The current paper extends our previous studies by describing the morphologic changes that occurred within each group of dogs studied. More than 100 glomeruli from the renal cortex of each dog were evaluated for increases in mesangial volume fraction (V(v)), glomerulosclerosis (GS) and arteriolar hyalinosis. The interstitium was also evaluated for associated changes. Increases in V(v) were attenuated in all treated groups (0.28 ± 0.04, DM alone versus 0.16 ± 0.05 L; 0.21 ± 0.07, TA-3090; 0.19 ± 0.06 μm2/μm2, L + TA 3090; P < 0.05) compared to untreated DM. An attenuated increase in V(v) also correlated with a blunted rise in proteinuria in Groups III (r = 0.79) and V (r = 0.81) but not Group IV (r = 0.29). Development of focal GS was blunted in all treated groups; however, global GS was fourfold greater in Group IV compared to untreated DM. The degree of interstitial fibrosis also correlated with the degree of global GS. These data support the concept that both a converting enzyme inhibitor and heart rate lowering calcium antagonist attenuate morphologic progression of diabetic renal disease. When used alone, however, the calcium antagonist increases development of global GS, an effect that appears to be independent of blood pressure control.