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.