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Poly(ADP-Ribose) Polymerase Inhibitors Ameliorate Nephropathy of Type 2 Diabetic Lepr^db/db Mice

Csaba Szabó¹, Alisha Biser², Rita Benk³, Erwin Böttinger⁴, and Katalin Suszták²

¹ Department of Surgery, University of Medicine and Dentistry of New Jersey, Newark, New Jersey
² Division of Nephrology, Department of Medicine, Albert Einstein College of Medicine, Bronx, New York
³ Department of Human Physiology and Clinical Experimental Research, Semmelweis University Medical School, Budapest, Hungary
⁴ Department of Medicine, Mount Sinai School of Medicine, New York, New York

Address correspondence and reprint requests to Katalin Susztak, Division of Nephrology, Albert Einstein College of Medicine, Bronx, NY 10461. E-mail: ksusztak{at}aecom.yu.edu

Abbreviations: ELISA, enzyme-linked immunosorbent assay; IB, inhibitor of B; NFB; nuclear factor-B; PARP, poly(ADP-ribose) polymerase; PAS, periodic acid Schiff; ROS, reactive oxygen species

The activation of the poly(ADP-ribose) polymerase (PARP) plays an important role in the pathophysiology of various diseases associated with oxidative stress. We found increased amounts of poly(ADP) ribosylated proteins in diabetic kidneys of Lepr^db/db (BKsJ) mice, suggesting increased PARP activity. Therefore, we examined the effects of two structurally unrelated PARP inhibitors (INO-1001 and PJ-34) on the development of diabetic nephropathy of Lepr^db/db (BKsJ) mice, an experimental model of type 2 diabetes. INO-1001 and PJ-34 were administered in the drinking water to Lepr^db/db mice. Both INO-1001 and PJ-34 treatment ameliorated diabetes-induced albumin excretion and mesangial expansion, which are hallmarks of diabetic nephropathy. PARP inhibitors decreased diabetes-induced podocyte depletion in vivo and blocked hyperglycemia-induced podocyte apoptosis in vitro. High glucose treatment of podocytes in vitro led to an early increase of poly(ADP) ribosylated modified protein levels. Reactive oxygen species (ROS) generation appears to be a downstream target of hyperglycemia-induced PARP activation, as PARP inhibitors blocked the hyperglycemia-induced ROS generation in podocytes. INO-1001 and PJ-34 also normalized the hyperglycemia-induced mitochondrial depolarization. PARP blockade by INO-1001 and PJ-34 prevented hyperglycemia-induced nuclear factor-B (NFB) activation of podocytes, and it was made evident by the inhibitor of B phosphorylation and NFB p50 nuclear translocation. Our results indicate that hyperglycemia-induced PARP activation plays an important role in the pathogenesis of glomerulopathy associated with type 2 diabetes and could serve as a novel therapeutic target.

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