title: Nicorandil, a K(atp) channel opener, alleviates chronic renal injury by targeting podocytes and macrophages.
abstract: Nicorandil exhibits a protective effect in the vascular system, which is thought to be due to vasodilatation from opening ATP-dependent potassium channels and donation of nitric oxide. Recently, nicorandil was shown to be renoprotective in models of acute kidney injury and glomerulonephritis. However, the specific mechanisms of renoprotection are unclear. We evaluated the effect of nicorandil on the rat remnant kidney model of chronic kidney disease. Blood pressure was unchanged by a 10-wk course of nicorandil, while albuminuria was significantly reduced. Glomerular injury and tubulointerstitial injury were also ameliorated by nicorandil. Oxidative stress, as noted by renal nitrotyrosine level and urine 8-hydroxy-2'-deoxyguanosine, were elevated in this model and was significantly reduced by nicorandil treatment. Treatment was associated with maintenance of the mitochondrial antioxidant, manganese SOD, in podocytes and with suppression of xanthine oxidase expression in infiltrating macrophages. Interestingly, these two cell types express sulfonylurea receptor 2 (SUR2), a binding site of nicorandil in the ATP-dependent K channel. Consistently, we found that stimulating SUR2 with nicorandil prevented angiotensin II-mediated upregulation of xanthine oxidase in the cultured macrophage, while xanthine oxidase expression was rather induced by blocking SUR2 with glibenclamide. In conclusion, nicorandil reduces albuminuria and ameliorates renal injury by blocking oxidative stress in chronic kidney disease.
authors.affiliation: Division of Renal Diseases and Hypertension, Univ. of Colorado Denver, C281, 12900E 19th Ave., Aurora, CO 80045, USA.
authors.forename: Yoshifuru
authors.initials: Y
authors.lastname: Tamura
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Tanabe
authors.forename: Wataru
authors.initials: W
authors.lastname: Kitagawa
authors.forename: Shunya
authors.initials: S
authors.lastname: Uchida
authors.forename: George F
authors.initials: GF
authors.lastname: Schreiner
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Johnson
authors.forename: Takahiko
authors.initials: T
authors.lastname: Nakagawa
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000419:Albuminuria / Q000517:prevention & control; D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D018450:Disease Progression; D007150:Immunohistochemistry; D054086:KATP Channels / Q000819:agonists*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D007676:Kidney Failure, Chronic / Q000188:drug therapy* / Q000473:pathology; D007678:Kidney Glomerulus / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008297:Male; D051379:Mice; D009395:Nephritis, Interstitial / Q000473:pathology / Q000517:prevention & control; D020108:Nicorandil / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D016612:Paraffin Embedding; D024661:Potassium Channels, Inwardly Rectifying / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011955:Receptors, Drug / Q000378:metabolism; D064233:Sulfonylurea Receptors; D014969:Xanthine Oxidase / Q000096:biosynthesis
chemical_list: D018528:ATP-Binding Cassette Transporters; C577512:Abcc9 protein, rat; D054086:KATP Channels; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors; D020108:Nicorandil; D009569:Nitric Oxide; D014969:Xanthine Oxidase