Poly(ADP-ribose) polymerase (PARP) inhibition counteracts multiple manifestations of kidney disease in long-term streptozotocin-diabetic rat model

Hanna Shevalye, Roman Stavniichuk, Weizheng Xu, Jie Zhang, Sergey Lupachyk, Yury Maksimchyk, Viktor R. Drel, Elizabeth Z. Floyd, Barbara Slusher, Irina G. Obrosova

Research output: Contribution to journalArticle

Abstract

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 1 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-20-deoxyguanosine excretion, and renal concentrations of transforming growth factor-b1, 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-20-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-β1, 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.

Original languageEnglish (US)
Pages (from-to)1007-1014
Number of pages8
JournalBiochemical Pharmacology
Volume79
Issue number7
DOIs
StatePublished - Apr 1 2010
Externally publishedYes

Keywords

  • Diabetic nephropathy
  • Oxidative-nitrosative stress
  • Poly(ADP-ribose) polymerase
  • Streptozotocin-diabetic rat
  • Transforming growth factor-β
  • Vascular endothelial growth factor

ASJC Scopus subject areas

  • Biochemistry
  • Pharmacology

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