Unlike each drug alone, lisinopril if combined with avosentan promotes regression of renal lesions in experimental diabetes

Abstract

In the present study, we evaluated the effect of simultaneously blocking angiotensin II synthesis and endothelin (ET)-1 activity as a multimodal intervention to implement renoprotection in overt diabetic nephropathy. Mechanisms underlying combined therapy effectiveness were addressed by investigating podocyte structure and function and glomerular barrier size-selective properties. Uninephrectomized rats made diabetic by streptozotocin received orally placebo, lisinopril (12.5 mg/l), the ET(A) receptor antagonist avosentan (30 mg/kg), or their combination from 4 (when animals had proteinuria) to 8 mo. Proteinuria, renal damage, podocyte number, nephrin expression, and glomerular size selectivity by graded-size Ficoll molecule fractional clearance were assessed. Combined therapy normalized proteinuria, provided complete protection from tubulointerstitial damage, and induced regression of glomerular lesions, while only a partial renoprotection was achieved by each drug alone. Lisinopril plus avosentan restored to normal values the number of podocytes. Single therapies only limited podocyte depletion. Defective nephrin expression of diabetes was prevented by each drug. Altered glomerular size selectivity to large macromolecules of diabetic rats was remarkably improved by lisinopril and the combined treatment. Avosentan ameliorated peritubular capillary architecture and reduced interstitial inflammation and fibrosis. The ACE inhibitor and ET(A) receptor antagonist induced regression of glomerular lesions in overt diabetic nephropathy. Regression of renal disease was conceivably the result of the synergistic effect of the ACE inhibitor of preserving glomerular permselective properties and the ET(A) antagonist in improving tubulointerstitial changes. These findings provide mechanistic insights to explain the antiproteinuric effect of this combined therapy in diabetes.

Addition of Atrasentan to Renin-Angiotensin System Blockade Reduces Albuminuria in Diabetic Nephropathy

“…These changes coincided with increased podocyte nephrin expression, decreased accumulation of TGF␤ and collagen III, reduced macrophage infiltration, and increased expression of matrix metalloproteinase-9, the enzyme principally involved with matrix degradation. 21 Despite the controlled and double-blinded design of this study, the limitations of small sample size, short duration of treatment, and absence of ambulatory BP readings require that a larger and longer study be performed for confirmation. The study was also limited by the absence of quantitative measures of renal hemodynamics to quantify potential changes in filtration fraction and renal vascular resistance.…”

“…19 ET A R antagonists may directly attenuate podocyte dysfunction through downregulation of TGF␤ and inhibition of macrophage infiltration. 20 In a recent study of a type 1 DN model, 21 the addition of an ET A R antagonist to RAS blockade in animals with established DN resulted in reduced albuminuria and regression of glomerulosclerosis. These changes coincided with increased podocyte nephrin expression, decreased accumulation of TGF␤ and collagen III, reduced macrophage infiltration, and increased expression of matrix metalloproteinase-9, the enzyme principally involved with matrix degradation.…”

Renal Allograft Fibrosis: Biology and Therapeutic Targets

“…Although not explored extensively in native kidneys, in a number of renal glomerular diseases, regression of glomerulosclerosis has been described during antagonism of the renin-angiotensin-and/or endothelin-1 system (354)(355)(356). However, in glomeruli, regression has usually been defined as removal of early, excess matrix and the re-establishment of glomerular capillaries and the mesangium.…”

Podocyte Mitosis – A Catastrophe

“…These events are accompanied by and likely underlie the regression of glomerulosclerosis [100-102] . Regression of renal disease with remodeling of glomerular architecture has been reported in experimental animal models, and clinically in patients with different types of glomerular disorders who have received prolonged treatment with angiotensin converting enzyme inhibitors [102-104]. These results cannot simply be explained through the protective effects of angiotensin converting enzyme inhibitors on podocyte loss, but rather suggest that novel podocytes can potentially be generated.…”