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This Article Full Text Full Text (PDF) All Versions of this Article: 297/5/F1448    most recent 00340.2009v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Gagliardini, E. Articles by Benigni, A. PubMed PubMed Citation Articles by Gagliardini, E. Articles by Benigni, A.

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

¹Mario Negri Institute for Pharmacological Research, ; ²Mechanical and Industrial Engineering Department, University of Bergamo, and ; ³Unit of Nephrology and Dialysis, Azienda Ospedaliera Ospedali Riuniti di Bergamo, Bergamo, Italy

Submitted June 16, 2009 ; accepted in final form August 7, 2009

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.

diabetic nephropathy; ACE inhibition; endothelin receptor antagonist; glomerular filtration barrier; podocytes