title: Modulation of renal superoxide dismutase by telmisartan therapy in C57BL/6-Ins2(Akita) diabetic mice.
abstract: Renal superoxide excess, which is induced by an imbalance of the superoxide-producing enzyme NAD(P)H oxidase and the superoxide-scavenging enzyme superoxide dismutase (SOD) under hyperglycemia, increases oxidative stress and contributes to the development of diabetic nephropathy. In this study, we treated non-obese and hypoinsulinemic C57BL/6-Ins2(Akita) (C57BL/6-Akita) diabetic mice with telmisartan (5 mg kg(-1) per day), an angiotensin II type 1 receptor blocker, or amlodipine (5 mg kg(-1) per day), a calcium channel blocker, for 4 weeks and compared the effects of these two anti-hypertensive drugs on renal NAD(P)H oxidase, SOD and transcription factor Nrf2 (NF-E2-related factor 2), which is known to upregulate several antioxidant enzymes including SOD. Vehicle-treated C57BL/6-Akita mice exhibited higher renal NAD(P)H oxidase and lower renal SOD activity with increased levels of renal superoxide than the C57BL/6-wild-type non-diabetic mice. Interestingly, telmisartan treatment not only reduced NAD(P)H oxidase activity but also enhanced SOD activity in C57BL/6-Akita mouse kidneys, leading to a reduction of renal superoxide levels. Furthermore, telmisartan-treated C57BL/6-Akita mice increased the renal protein expression of SOD and Nrf2. In parallel with the reduction of renal superoxide levels, a reduction of urinary albumin levels and a normalization of elevated glomerular filtration rate were observed in telmisartan-treated C57BL/6-Akita mice. In contrast, treatment with amlodipine failed to modulate renal NAD(P)H oxidase, SOD and Nrf2. Finally, treatment of C57BL/6-Akita mice with apocynin, an NAD(P)H oxidase inhibitor, also increased the renal protein expression of SOD and Nrf2. Collectively, our data suggest that NAD(P)H oxidase negatively regulates renal SOD, possibly by downregulation of Nrf2, and that telmisartan could upregulate renal SOD by the suppression of NAD(P)H oxidase and subsequent upregulation of Nrf2, leading to the amelioration of renal oxidative stress and diabetic renal changes.
authors.affiliation: Division of Endocrinology, Metabolism and Geriatric Medicine, Akita University Graduate School of Medicine, Akita, Japan. hirofuji@gipc.akita-u.ac.jp
authors.forename: Hiroki
authors.initials: H
authors.lastname: Fujita
authors.forename: Hiromi
authors.initials: H
authors.lastname: Fujishima
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Morii
authors.forename: Takuya
authors.initials: T
authors.lastname: Sakamoto
authors.forename: Koga
authors.initials: K
authors.lastname: Komatsu
authors.forename: Mihoko
authors.initials: M
authors.lastname: Hosoba
authors.forename: Takuma
authors.initials: T
authors.lastname: Narita
authors.forename: Keiko
authors.initials: K
authors.lastname: Takahashi
authors.forename: Takamune
authors.initials: T
authors.lastname: Takahashi
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Yamada
mesh_terms: D000098:Acetophenones / Q000494:pharmacology; D017311:Amlodipine / Q000494:pharmacology; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001562:Benzimidazoles / Q000494:pharmacology*; D001565:Benzoates / Q000494:pharmacology*; D001774:Blood Chemical Analysis; D001786:Blood Glucose / Q000378:metabolism; D015153:Blotting, Western; D003920:Diabetes Mellitus / Q000201:enzymology* / Q000235:genetics*; D003928:Diabetic Nephropathies / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006943:Hyperglycemia / Q000150:complications / Q000378:metabolism; D007150:Immunohistochemistry; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019255:NADPH Oxidases / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000096:biosynthesis / Q000235:genetics; D013482:Superoxide Dismutase / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism; D000077333:Telmisartan
chemical_list: D000098:Acetophenones; D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001565:Benzoates; D001786:Blood Glucose; D004791:Enzyme Inhibitors; D051267:NF-E2-Related Factor 2; D013481:Superoxides; D017311:Amlodipine; C056165:acetovanillone; D013482:Superoxide Dismutase; D019255:NADPH Oxidases; D015232:Dinoprostone; D000077333:Telmisartan
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