Targeted Therapies in Diabetic Nephropathy Examined

Poly(ADP-ribose) polymerase may benefit nephropathy associated with type 1 diabetes
By Eric Metcalf
HealthDay Reporter

MONDAY, Nov. 9 (HealthDay News) -- Poly(ADP-ribose) polymerase (PARP) activation appears to play a role in numerous changes associated with early kidney disease seen in type 1 diabetes, according to research published online Oct. 23 in Endocrinology.

Viktor R. Drel, Ph.D., of the Louisiana State University System in Baton Rouge, and colleagues analyzed data from rats that were maintained as controls or rendered diabetic with streptozotocin. Diabetic rats were treated with the PARP inhibitors 1,5- isoquinolinediol (ISO) or 10-(4-methyl-piperazin-1-ylmethyl)-2H-7-oxa-1,2-diaza-benzo[de]anthracen-3-one (GPI-15427) for 10 weeks, or left untreated.

In untreated diabetic rats, the researchers found that urinary albumin excretion was elevated approximately four-fold compared to nondiabetic controls, but ISO and GPI-15427 largely prevented the increase. In diabetic rats, renal concentrations of transforming growth factor-β1, vascular endothelial growth factor, tumor necrosis factor-α, lipid peroxidation products, nitrotyrosine, and monocyte chemoattractant protein-1 were all increased, but these changes were inhibited by the PARP inhibitors.

"In conclusion, PARP activation contributes to advanced glycation end product formation, oxidative-nitrosative stress, and proinflammatory response in the diabetic kidney and triggers multiple mechanisms leading to albuminuria, mesangial expansion, and podocyte loss in early type 1 diabetic nephropathy," the authors write.

Two co-authors formerly worked at MGI Pharma, which is now part of Eisai Inc., a company developing PARP inhibitors; and another co-author currently works at Eisai Inc.

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