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Nitrosonifedipine ameliorates the progression of type 2 diabetic nephropathy by exerting antioxidative effects.

ABSTRACT: 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.

SUBMITTER: Ishizawa K

PROVIDER: S-EPMC3904885 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Nitrosonifedipine ameliorates the progression of type 2 diabetic nephropathy by exerting antioxidative effects.

Ishizawa Keisuke K Izawa-Ishizawa Yuki Y Yamano Noriko N Urushihara Maki M Sakurada Takumi T Imanishi Masaki M Fujii Shoko S Nuno Asami A Miyamoto Licht L Kihira Yoshitaka Y Ikeda Yasumasa Y Kagami Shoji S Kobori Hiroyuki H Tsuchiya Koichiro K Tamaki Toshiaki T

PloS one 20140128 1

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 b ...[more]

PMID: 24489716

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Project description:Adiponectin exerts renoprotective effects against diabetic nephropathy (DN) by activating the AMP-activated protein kinase (AMPK)/peroxisome proliferative-activated receptor-? (PPAR?) pathway through adiponectin receptors (AdipoRs). AdipoRon is an orally active synthetic adiponectin receptor agonist. We investigated the expression of AdipoRs and the associated intracellular pathways in 27 patients with type 2 diabetes and examined the effects of AdipoRon on DN development in male C57BLKS/J db/db mice, glomerular endothelial cells (GECs), and podocytes. The extent of glomerulosclerosis and tubulointerstitial fibrosis correlated with renal function deterioration in human kidneys. Expression of AdipoR1, AdipoR2, and Ca2+/calmodulin-dependent protein kinase kinase-? (CaMKK?) and numbers of phosphorylated liver kinase B1 (LKB1)- and AMPK-positive cells significantly decreased in the glomeruli of early stage human DN. AdipoRon treatment restored diabetes-induced renal alterations in db/db mice. AdipoRon exerted renoprotective effects by directly activating intrarenal AdipoR1 and AdipoR2, which increased CaMKK?, phosphorylated Ser431LKB1, phosphorylated Thr172AMPK, and PPAR? expression independently of the systemic effects of adiponectin. AdipoRon-induced improvement in diabetes-induced oxidative stress and inhibition of apoptosis in the kidneys ameliorated relevant intracellular pathways associated with lipid accumulation and endothelial dysfunction. In high-glucose-treated human GECs and murine podocytes, AdipoRon increased intracellular Ca2+ levels that activated a CaMKK?/phosphorylated Ser431LKB1/phosphorylated Thr172AMPK/PPAR? pathway and downstream signaling, thus decreasing high-glucose-induced oxidative stress and apoptosis and improving endothelial dysfunction. AdipoRon further produced cardioprotective effects through the same pathway demonstrated in the kidney. Our results show that AdipoRon ameliorates GEC and podocyte injury by activating the intracellular Ca2+/LKB1-AMPK/PPAR? pathway, suggesting its efficacy for treating type 2 diabetes-associated DN.

Dataset Information

Nitrosonifedipine ameliorates the progression of type 2 diabetic nephropathy by exerting antioxidative effects.

Publications

Nitrosonifedipine ameliorates the progression of type 2 diabetic nephropathy by exerting antioxidative effects.

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