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

Katsuyuki Tanabe, Miguel A. Lanaspa, Wataru Kitagawa, Christopher J. Rivard, Makoto Miyazaki, Jelena Klawitter, George F. Schreiner, Moin A. Saleem, Peter W. Mathieson, Hirofumi Makino, Richard J. Johnson, Takahiko Nakagawa

Research output: Contribution to journalArticle

30 Citations (Scopus)

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.

Original languageEnglish
JournalAmerican Journal of Physiology - Renal Physiology
Volume302
Issue number9
DOIs
Publication statusPublished - May 1 2012

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Nicorandil
Diabetic Nephropathies
Podocytes
Therapeutics
Adenosine Triphosphate
Blood Pressure
Experimental Diabetes Mellitus
Nitric Oxide Donors
Nitric Oxide Synthase Type III
Proteinuria
Oxidants
Blood Glucose
Histology
Oxidative Stress
Antioxidants
Clinical Trials

Keywords

  • ATP-dependent K channel
  • Endothelial dysfunction
  • Podocyte
  • Sulfo-nylurea receptor

ASJC Scopus subject areas

  • Physiology
  • Urology

Cite this

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

In: American Journal of Physiology - Renal Physiology, Vol. 302, No. 9, 01.05.2012.

Research output: Contribution to journalArticle

Tanabe, K, Lanaspa, MA, Kitagawa, W, Rivard, CJ, Miyazaki, M, Klawitter, J, Schreiner, GF, Saleem, MA, Mathieson, PW, Makino, H, Johnson, RJ & Nakagawa, T 2012, 'Nicorandil as a novel therapy for advanced diabetic nephropathy in the eNOS-deficient mouse', American Journal of Physiology - Renal Physiology, vol. 302, no. 9. https://doi.org/10.1152/ajprenal.00596.2011
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. / Nicorandil as a novel therapy for advanced diabetic nephropathy in the eNOS-deficient mouse. In: American Journal of Physiology - Renal Physiology. 2012 ; Vol. 302, No. 9.
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