TY - JOUR
T1 - Poly(ADP-ribose) polymerase (PARP) inhibition counteracts multiple manifestations of kidney disease in long-term streptozotocin-diabetic rat model
AU - Shevalye, Hanna
AU - Stavniichuk, Roman
AU - Xu, Weizheng
AU - Zhang, Jie
AU - Lupachyk, Sergey
AU - Maksimchyk, Yury
AU - Drel, Viktor R.
AU - Floyd, Elizabeth Z.
AU - Slusher, Barbara
AU - Obrosova, Irina G.
N1 - Funding Information:
The study was supported by the Juvenile Diabetes Research Foundation International Grant 1-2005-223 , National Institutes of Health Grants DK070720 , DK074517 , and DK077141 , and American Diabetes Association Grant (all to I.G.O.). The authors thank Dr. Ivan A. Pavlov for expert technical assistance.
PY - 2010/4/1
Y1 - 2010/4/1
N2 - 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.
AB - 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.
KW - Diabetic nephropathy
KW - Oxidative-nitrosative stress
KW - Poly(ADP-ribose) polymerase
KW - Streptozotocin-diabetic rat
KW - Transforming growth factor-β
KW - Vascular endothelial growth factor
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U2 - 10.1016/j.bcp.2009.11.018
DO - 10.1016/j.bcp.2009.11.018
M3 - Article
C2 - 19945439
AN - SCOPUS:77449124908
SN - 0006-2952
VL - 79
SP - 1007
EP - 1014
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
IS - 7
ER -