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

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−1d−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-β1, 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-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.

A metabolomic study of low estimated GFR in non-proteinuric type 2 diabetes mellitus

“…Benzamide has been shown to be an endogenous inhibitor of poly(ADP-ribose) polymerase-1 (PARP-1) [25,26], a key enzyme that has been strongly implicated in causing diabetes-associated endothelial dysfunction [27]. Pharmacological inhibition of PARP-1 ameliorated various features associated with nephropathy in both experimental models of type 1 and type 2 diabetes, including albuminuria [28,29]. Urinary albumin and protein excretion were reduced in the streptozotocin-diabetic mouse model with the endogenous Parp1 gene constitutively ablated by gene knockout [30].…”

WldSameliorates renal injury in a type 1 diabetic mouse model

“…NAD ϩ depletion and energy failure can be induced by ROS-trigged PARP activation. PARP inhibition (INO-1001, PJ34, 1,5-isoquinolinediol, and GPI-15,427) and PARP-1 gene deficiency are examples of nephroprotection (9,40,41,43). Moreover, a higher NAD or NAD ϩ /NADH ratio can activate the sirtuin 1 (SIRT1) pathway (3,47), which is a known renal cytoprotector responding to aging and stress (51).…”

On PAR with PARP: cellular stress signaling through poly(ADP-ribose) and PARP-1

“…Indeed, PARP-1 and other PARP family members have proven to be effectively inhibited by a broad array of small molecules (Rouleau et al 2010). The therapeutic application of PARP inhibitors has received a considerable amount of attention recently because of their potential utility in the treatment of cancers, but the possible therapeutic applications of PARP inhibitors extend far beyond cancer therapy to other types of stress-related diseases, such as cardiovascular diseases, stroke, metabolic disorders, diabetes, and autoimmunity, and virtually any disease or condition with acute or chronic inflammation as a root cause (Masutani et al 2005;Mota et al 2005;Pacher and Szabo 2007;Shevalye et al 2010;Ford and Lee 2011;Underhill et al 2011).…”

“…In this regard, PARP inhibitors have been explored as therapeutics to prevent cell death, tissue damage, and dysfunction associated with aging-or oxidative damage-related pathologies, such as cardiovascular diseases, autoimmune and inflammatory diseases, neurodegenerative diseases, stroke, and diabetes and its associated complications ( Fig. 7; Masutani et al 2005;Mota et al 2005;Pacher and Szabo 2007;Shevalye et al 2010;Ford and Lee 2011;Underhill et al 2011). The recent discovery of the metabolic functions of PARP-1 and PARP-2, in concert with SIRT1, based on knockout mouse models suggests a therapeutic potential of PARP inhibitors in metabolic disorders (Bai et al 2011a,b).…”