Nicorandil as a novel therapy for advanced diabetic nephropathy in the eNOS-deficient mouse

• Published in: American journal of physiology. Renal physiology 2012-05, Vol.302 (9), p.F1151-F1160
• Main Authors: Tanabe, Katsuyuki, Lanaspa, Miguel A, Kitagawa, Wataru, Rivard, Christopher J, Miyazaki, Makoto, Klawitter, Jelena, Schreiner, George F, Saleem, Moin A, Mathieson, Peter W, Makino, Hirofumi, Johnson, Richard J, Nakagawa, Takahiko
• Format: Article
• Language: English
• Subjects: Adenosine triphosphatase; Animals; Antioxidants; Antioxidants - pharmacology; Antioxidants - therapeutic use; Apoptosis - drug effects; Apoptosis - physiology; Blood Pressure - drug effects; Blood Pressure - physiology; Cells, Cultured; Diabetes; Diabetes Mellitus, Experimental - chemically induced; Diabetes Mellitus, Experimental - complications; Diabetic Nephropathies - drug therapy; Diabetic Nephropathies - etiology; Diabetic Nephropathies - physiopathology; Disease Models, Animal; Disease Progression; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Nicorandil - pharmacology; Nicorandil - therapeutic use; Nitric oxide; Nitric Oxide Donors - pharmacology; Nitric Oxide Donors - therapeutic use; Nitric Oxide Synthase Type III - deficiency; Nitric Oxide Synthase Type III - genetics; Oxidative stress; Oxidative Stress - drug effects; Oxidative Stress - physiology; Podocytes - cytology; Podocytes - drug effects; Podocytes - metabolism; Reactive Oxygen Species - metabolism; Rodents; Severity of Illness Index; Streptozocin - adverse effects
• ISSN: 1931-857X; 1522-1466
• DOI: 10.1152/ajprenal.00596.2011

Nicorandil is an orally available drug that can act as a nitric oxide donor, an antioxidant, and an ATP-dependent K channel activator. We hypothesized that it may have a beneficial role in treating diabetic nephropathy. We administered nicorandil to a model of advanced diabetic nephropathy (the streptozotocin-induced diabetes in mice lacking endothelial nitric oxide synthase, eNOSKO); controls included diabetic eNOS KO mice without nicorandil and nondiabetic eNOS KO mice treated with either nicorandil or vehicle. Mice were treated for 8 wk. Histology, blood pressure, and renal function were determined. Additional studies involved examining the effects of nicorandil on cultured human podocytes. Here, we found that nicorandil did not affect blood glucose levels, blood pressure, or systemic endothelial function, but significantly reduced proteinuria and glomerular injury (mesangiolysis and glomerulosclerosis). Nicorandil protected against podocyte loss and podocyte oxidative stress. Studies in cultured podocytes showed that nicorandil likely protects against glucose-mediated oxidant stress via the ATP-dependent K channel as opposed to its NO-stimulating effects. In conclusion, nicorandil may be beneficial in diabetic nephropathy by preserving podocyte function. We recommend clinical trials to determine whether nicorandil may benefit diabetic nephropathy or other conditions associated with podocyte dysfunction.