title: Nicorandil as a novel therapy for advanced diabetic nephropathy in the eNOS-deficient mouse.
abstract: 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.
authors.affiliation: Division of Renal Diseases and Hypertension, University of Colorado Denver, C281, 12900E 19th Ave., Aurora, CO 80045, USA.
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Tanabe
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Lanaspa
authors.forename: Wataru
authors.initials: W
authors.lastname: Kitagawa
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Rivard
authors.forename: Makoto
authors.initials: M
authors.lastname: Miyazaki
authors.forename: Jelena
authors.initials: J
authors.lastname: Klawitter
authors.forename: George F
authors.initials: GF
authors.lastname: Schreiner
authors.forename: Moin A
authors.initials: MA
authors.lastname: Saleem
authors.forename: Peter W
authors.initials: PW
authors.lastname: Mathieson
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Makino
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Johnson
authors.forename: Takahiko
authors.initials: T
authors.lastname: Nakagawa
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000150:complications; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D004195:Disease Models, Animal; D018450:Disease Progression; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020108:Nicorandil / Q000494:pharmacology / Q000627:therapeutic use*; D020030:Nitric Oxide Donors / Q000494:pharmacology / Q000627:therapeutic use*; D052250:Nitric Oxide Synthase Type III / Q000172:deficiency* / Q000235:genetics; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D050199:Podocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D012720:Severity of Illness Index; D013311:Streptozocin / Q000009:adverse effects
chemical_list: D000975:Antioxidants; D020030:Nitric Oxide Donors; D017382:Reactive Oxygen Species; D020108:Nicorandil; D013311:Streptozocin; D052250:Nitric Oxide Synthase Type III