Journal
BIOCHEMICAL PHARMACOLOGY
Volume 79, Issue 7, Pages 1007-1014Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bcp.2009.11.018
Keywords
Poly(ADP-ribose) polymerase; Diabetic nephropathy; Streptozotocin-diabetic rat; Oxidative-nitrosative stress; vascular endothelial growth factor; Transforming growth factor-beta
Categories
Funding
- Juvenile Diabetes Research Foundation International [1-2005-223]
- National Institutes of Health [DK070720, DK074517, DK077141]
- American Diabetes Association Grant
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK074517, P30DK072476, R21DK070720, R01DK077141] Funding Source: NIH RePORTER
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Evidence for the important role for poly(ADP-ribose) polymerase (PARP) in the pathogenesis of diabetic nephropathy is emerging. We previously reported that PARP inhibitors counteract early Type 1 diabetic nephropathy. This study evaluated the role for PARP in kidney disease in long-term Type I diabetes. Control and streptozotocin-diabetic rats were maintained with or without treatment with the PARP inhibitor 10-(4-methyl-piperazin-1-ylmethyl)-2H-7-oxa-1,2-diaza-benzo[de] anthracen-3-one (GPI-15,427, Eisai Inc.), 30 mg kg(-1) d(-1), for 26 weeks after first 2 weeks without treatment. PARP activity in the renal cortex was assessed by Western blot analysis of poly(ADP-ribosyl)ated proteins. Urinary albumin, isoprostane, and 8-hydroxy-2'-deoxyguanosine excretion, and renal concentrations of transforming growth factor-beta(1), vascular endothelial growth factor, soluble intercellular adhesion molecule-1, fibronectin, and nitrotyrosine were evaluated by ELISA, and urinary creatinine and renal lipid peroxidation products by colorimetric assays. PARP inhibition counteracted diabetes-associated increase in renal cortex poly(ADP-ribosyl)ated protein level. Urinary albumin, isoprostane, and 8-hydroxy-2'-deoxyguanosine excretions and urinary albumin/creatinine ratio were increased in diabetic rats, and all these changes were at least partially prevented by GPI-15,427 treatment. PARP inhibition counteracted diabetes-induced renal transforming growth factor-beta(1), vascular endothelial growth factor, and fibronectin, but not soluble intercellular adhesion molecule-1 and nitrotyrosine, accumulations. Lipid peroxidation product concentrations were indistinguishable among control and diabetic rats maintained with or without GPI-15,427 treatment. In conclusion, PARP activation plays an important role in kidney disease in long-term diabetes. These findings provide rationale for development and further studies of PARP inhibitors and PARP inhibitor-containing combination therapies, for prevention and treatment of diabetic nephropathy. (C) 2009 Elsevier Inc. All rights reserved.
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