Poly(ADP-ribose) polymerase inhibitors ameliorate nephropathy of type 2 diabetic Leprdb/db mice.
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-kappaB (NFkappaB) activation of podocytes, and it was made evident by the inhibitor of kappaBalpha phosphorylation and NFkappaB 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.
Szabó
Csaba
C
Division of Nephrology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Biser
Alisha
A
Benko
Rita
R
Böttinger
Erwin
E
Suszták
Katalin
K
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001794:Blood Pressure; D001835:Body Weight; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology*; D003928:Diabetic Nephropathies / Q000517:prevention & control*; D004789:Enzyme Activation; D007211:Indoles / Q000494:pharmacology*; D007668:Kidney / Q000503:physiopathology; D051379:Mice; D010616:Phenanthrenes / Q000494:pharmacology*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics*; D054411:Receptors, Leptin
C491685:INO 1001; D007211:Indoles; C434926:N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride; D010616:Phenanthrenes; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D017382:Reactive Oxygen Species; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; D011065:Poly(ADP-ribose) Polymerases