Nitrosonifedipine ameliorates the progression of type 2 diabetic nephropathy by exerting antioxidative effects.
Diabetic nephropathy (DN) is the major cause of end-stage renal failure. Oxidative stress is implicated in the pathogenesis of DN. Nitrosonifedipine (NO-NIF) is a weak calcium channel blocker that is converted from nifedipine under light exposure. Recently, we reported that NO-NIF has potential as a novel antioxidant with radical scavenging abilities and has the capacity to treat vascular dysfunction by exerting an endothelial protective effect. In the present study, we extended these findings by evaluating the efficacy of NO-NIF against DN and by clarifying the mechanisms of its antioxidative effect. In a model of type 2 DN (established in KKAy mice), NO-NIF administration reduced albuminuria and proteinuria as well as glomerular expansion without affecting glucose metabolism or systolic blood pressure. NO-NIF also suppressed renal and systemic oxidative stress and decreased the expression of intercellular adhesion molecule (ICAM)-1, a marker of endothelial cell injury, in the glomeruli of the KKAy mice. Similarly, NO-NIF reduced albuminuria, oxidative stress, and ICAM-1 expression in endothelial nitric oxide synthase (eNOS) knockout mice. Moreover, NO-NIF suppressed urinary angiotensinogen (AGT) excretion and intrarenal AGT protein expression in proximal tubular cells in the KKAy mice. On the other hand, hyperglycemia-induced mitochondrial superoxide production was not attenuated by NO-NIF in cultured endothelial cells. These findings suggest that NO-NIF prevents the progression of type 2 DN associated with endothelial dysfunction through selective antioxidative effects.
Department of Medical Pharmacology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
Keisuke
K
Ishizawa
Department of Pharmacology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
Yuki
Y
Izawa-Ishizawa
Department of Pharmacology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
Noriko
N
Yamano
Department of Pediatrics, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
Maki
M
Urushihara
Department of Pharmacology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
Takumi
T
Sakurada
Department of Pharmacology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
Masaki
M
Imanishi
Department of Medical Pharmacology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
Shoko
S
Fujii
Department of Medical Pharmacology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
Asami
A
Nuno
Department of Medical Pharmacology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
Licht
L
Miyamoto
Department of Pharmacology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
Yoshitaka
Y
Kihira
Department of Pharmacology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
Yasumasa
Y
Ikeda
Department of Pediatrics, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
Shoji
S
Kagami
Department of Pharmacology, Faculty of Medicine, Kagawa University, Kagawa, Japan.
Hiroyuki
H
Kobori
Department of Medical Pharmacology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
Koichiro
K
Tsuchiya
Department of Pharmacology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
Toshiaki
T
Tamaki
D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use*; D002460:Cell Line; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009543:Nifedipine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D009603:Nitroso Compounds / Q000627:therapeutic use*; D018384:Oxidative Stress / Q000187:drug effects
D000975:Antioxidants; D009603:Nitroso Compounds; C539379:nitrosonifedipine; D052250:Nitric Oxide Synthase Type III; D009543:Nifedipine