Unlike each drug alone, lisinopril if combined with avosentan promotes regression of renal lesions in experimental diabetes.
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.
Gagliardini
Elena
E
Mario Negri Institute for Pharmacological Research, University of Bergamo, Bergamo, Italy. elena.gagliardini@marionegri.it
Corna
Daniela
D
Zoja
Carla
C
Sangalli
Fabio
F
Carrara
Fabiola
F
Rossi
Matteo
M
Conti
Sara
S
Rottoli
Daniela
D
Longaretti
Lorena
L
Remuzzi
Andrea
A
Remuzzi
Giuseppe
G
Benigni
Ariela
A
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002196:Capillaries / Q000473:pathology; D002452:Cell Count; D003921:Diabetes Mellitus, Experimental / Q000473:pathology; D003928:Diabetic Nephropathies / Q000401:mortality / Q000473:pathology / Q000517:prevention & control*; D004359:Drug Therapy, Combination; D065130:Endothelin A Receptor Antagonists; D007150:Immunohistochemistry; D007668:Kidney / Q000473:pathology; D007678:Kidney Glomerulus / Q000187:drug effects / Q000473:pathology; D008055:Lipids / Q000097:blood; D017706:Lisinopril / Q000627:therapeutic use*; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis / Q000235:genetics; D050199:Podocytes / Q000187:drug effects / Q000473:pathology; D011725:Pyridines / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000806:Angiotensin-Converting Enzyme Inhibitors; D065130:Endothelin A Receptor Antagonists; D008055:Lipids; D011725:Pyridines; D011743:Pyrimidines; D012333:RNA, Messenger; D017706:Lisinopril; D020780:Matrix Metalloproteinase 9; C484919:Avosentan