Long-term therapeutic effect of vitamin D analog doxercalciferol on diabetic nephropathy: strong synergism with AT1 receptor antagonist.

Abstract

The intrarenal renin-angiotensin system (RAS) plays a key role in the development of diabetic nephropathy. Recently, we showed that combination therapy with an AT(1) receptor blocker (ARB) and an activated vitamin D analog produced excellent synergistic effects against diabetic nephropathy, as a result of blockade of the ARB-induced compensatory renin increase. Given the diversity of vitamin D analogs, here we used a pro-drug vitamin D analog, doxercalciferol (1alpha-hydroxyvitamin D(2)), to further test the efficacy of the combination strategy in long-term treatment. Streptozotocin-induced diabetic DBA/2J mice were treated with vehicle, losartan, doxercalciferol (0.4 and 0.6 microg/kg), or losartan and doxercalciferol combinations for 20 wk. Vehicle-treated diabetic mice developed progressive albuminuria and glomerulosclerosis. Losartan alone moderately ameliorated kidney injury, with renin being drastically upregulated. A similar therapeutic effect was seen with doxercalciferol alone, which markedly suppressed renin and angiotensinogen expression. The losartan and doxercalciferol combination most effectively prevented albuminuria, restored glomerular filtration barrier structure, and dramatically reduced glomerulosclerosis in a dose-dependent manner. These effects were accompanied by blockade of intrarenal renin upregulation and ANG II accumulation. These data demonstrate an excellent therapeutic potential for doxercalciferol in diabetic renal disease and confirm the concept that blockade of the compensatory renin increase enhances the efficacy of RAS inhibition and produces synergistic therapeutic effects in combination therapy.

• Authors: Yan Zhang, Dilip K Deb, Juan Kong, Gang Ning, Yurong Wang, George Li, Yunzi Chen, Zhongyi Zhang, Stephen Strugnell, Yves Sabbagh, Cynthia Arbeeny, Yan Chun Li
• Journal: American journal of physiology. Renal physiology (Am J Physiol Renal Physiol) Vol. 297 Issue 3 Pg. F791-801 (Sep 2009) ISSN: 1522-1466 [Electronic] United States
• PMID: 19535571 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Angiotensin II Type 1 Receptor Blockers
• Cytokines
• Ergocalciferols
• Inflammation Mediators
• Vitamins
• Angiotensinogen
• Angiotensin II
• 1 alpha-hydroxyergocalciferol
• Renin
• Losartan

Topics

• Albuminuria (etiology, prevention & control)
• Angiotensin II (metabolism)
• Angiotensin II Type 1 Receptor Blockers (pharmacology)
• Angiotensinogen (metabolism)
• Animals
• Cytokines (metabolism)
• Diabetes Mellitus, Experimental (complications, drug therapy, metabolism, pathology)
• Diabetic Nephropathies (etiology, metabolism, pathology, prevention & control)
• Dose-Response Relationship, Drug
• Drug Synergism
• Drug Therapy, Combination
• Ergocalciferols (pharmacology)
• Fibrosis
• Glomerular Basement Membrane (drug effects, pathology)
• Inflammation Mediators (metabolism)
• Losartan (pharmacology)
• Macrophages (drug effects, pathology)
• Mice
• Mice, Inbred DBA
• Podocytes (drug effects, pathology)
• Renin (metabolism)
• Renin-Angiotensin System (drug effects, genetics)
• Time Factors
• Vitamins (pharmacology)