title: Combination of ACE inhibitor with nicorandil provides further protection in chronic kidney disease.
abstract: An inhibition in the renin-angiotensin system (RAS) is one of the most widely used therapies to treat chronic kidney disease. However, its effect is occasionally not sufficient and additional treatments may be required. Recently, we reported that nicorandil exhibited renoprotective effects in a mouse model of diabetic nephropathy. Here we examined if nicorandil can provide an additive protection on enalapril in chronic kidney disease. Single treatment with either enalapril or nicorandil significantly ameliorated glomerular and tubulointerstitial injury in the rat remnant kidney while the combination of these two compounds provided additive effects. In addition, an increase in oxidative stress in remnant kidney was also blocked by either enalapril or nicorandil while the combination of the drugs was more potent. A mechanism was likely due for nicorandil to preventing manganase superoxide dismutase (MnSOD) and sirtuin (Sirt)3 from being reduced in injured kidneys. A study with cultured podocytes indicated that the antioxidative effect could be mediated through sulfonylurea receptor (SUR) in the mitochondrial KATP channel since blocking SUR with glibenclamide reduced MnSOD and Sirt3 expression in podocytes. In conclusion, nicorandil may synergize with enalapril to provide superior protection in chronic kidney disease.
authors.affiliation: Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan;
authors.forename: Takeshi
authors.initials: T
authors.lastname: Shiraishi
authors.affiliation: Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan;
authors.forename: Yoshifuru
authors.initials: Y
authors.lastname: Tamura
authors.affiliation: Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan;
authors.forename: Kei
authors.initials: K
authors.lastname: Taniguchi
authors.affiliation: Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan;
authors.forename: Masato
authors.initials: M
authors.lastname: Higaki
authors.affiliation: Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan;
authors.forename: Shuko
authors.initials: S
authors.lastname: Ueda
authors.affiliation: Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan;
authors.forename: Tomoko
authors.initials: T
authors.lastname: Shima
authors.affiliation: Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan;
authors.forename: Michito
authors.initials: M
authors.lastname: Nagura
authors.affiliation: TMK Project, Medical Innovation Center, Kyoto University, Kyoto, Japan; and.
authors.forename: Takahiko
authors.initials: T
authors.lastname: Nakagawa
authors.affiliation: Division of Renal Diseases and Hypertension, University of Colorado Denver, Aurora, Colorado.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Johnson
authors.affiliation: Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan; teikyokidney@gmail.com.
authors.forename: Shunya
authors.initials: S
authors.lastname: Uchida
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D002460:Cell Line; D004195:Disease Models, Animal; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004656:Enalapril / Q000494:pharmacology*; D054086:KATP Channels / Q000187:drug effects / Q000378:metabolism; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D009392:Nephrectomy; D020108:Nicorandil / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects; D050199:Podocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D051436:Renal Insufficiency, Chronic / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D056566:Sirtuin 3 / Q000378:metabolism; D064233:Sulfonylurea Receptors / Q000187:drug effects / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism; D013997:Time Factors
chemical_list: C577508:Abcc8 protein, mouse; D000806:Angiotensin-Converting Enzyme Inhibitors; D000975:Antioxidants; D054086:KATP Channels; D026902:Potassium Channel Blockers; D064233:Sulfonylurea Receptors; D020108:Nicorandil; D004656:Enalapril; D013482:Superoxide Dismutase; D056566:Sirtuin 3
keywords: chronic kidney disease; enalapril; nicorandil; oxidative stress; remnant kidney