Poly(ADP-ribose) polymerase (PARP) inhibition counteracts multiple manifestations of kidney disease in long-term streptozotocin-diabetic rat model.
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.), 30mgkg(-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.
Shevalye
Hanna
H
Pennington Biomedical Research Center, Louisiana State University System, 6400 Perkins Road, Baton Rouge, LA 70808, United States.
Stavniichuk
Roman
R
Xu
Weizheng
W
Zhang
Jie
J
Lupachyk
Sergey
S
Maksimchyk
Yury
Y
Drel
Viktor R
VR
Floyd
Elizabeth Z
EZ
Slusher
Barbara
B
Obrosova
Irina G
IG
D000419:Albuminuria / Q000517:prevention & control; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D003921:Diabetes Mellitus, Experimental / Q000150:complications*; D003928:Diabetic Nephropathies / Q000517:prevention & control*; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005353:Fibronectins / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007672:Kidney Cortex / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009930:Organic Chemicals / Q000494:pharmacology / Q000627:therapeutic use*; D018384:Oxidative Stress / Q000187:drug effects; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D051381:Rats; D017208:Rats, Wistar; D013311:Streptozocin; D016212:Transforming Growth Factor beta / Q000502:physiology; D015430:Weight Gain / Q000187:drug effects
D001786:Blood Glucose; D004791:Enzyme Inhibitors; D005353:Fibronectins; D009930:Organic Chemicals; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D016212:Transforming Growth Factor beta; D018799:Intercellular Adhesion Molecule-1; D013311:Streptozocin; C502278:GPI 15427