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Title: Ablation of the N-type calcium channel ameliorates diabetic nephropathy with improved glycemic control and reduced blood pressure
Authors: Ohno, Shoko
Yokoi, Hideki  kyouindb  KAKEN_id
Mori, Kiyoshi
Kasahara, Masato
Kuwahara, Koichiro  KAKEN_id
Fujikura, Junji  kyouindb  KAKEN_id
Naito, Masaki
Kuwabara, Takashige
Imamaki, Hirotaka
Ishii, Akira  kyouindb  KAKEN_id
Saleem, Moin A.
Numata, Tomohiro
Mori, Yasuo  kyouindb  KAKEN_id
Nakao, Kazuwa
Yanagita, Motoko  kyouindb  KAKEN_id
Mukoyama, Masashi
Author's alias: 横井, 秀基
笠原, 正登
桑原, 宏一郎
藤倉, 純二
今牧, 博貴
柳田, 素子
Issue Date: 7-Jun-2016
Publisher: Nature Publishing Group
Journal title: Scientific Reports
Volume: 6
Thesis number: 27192
Abstract: Pharmacological blockade of the N-and L-type calcium channel lessens renal injury in kidney disease patients. The significance of specific blockade of α1 subunit of N-type calcium channel, Ca[v]2.2, in diabetic nephropathy, however, remains to be clarified. To examine functional roles, we mated Ca[v]2.2-/- mice with db/db (diabetic) mice on the C57BLKS background. Ca[v]2.2 was localized in glomeruli including podocytes and in distal tubular cells. Diabetic Ca[v]2.2-/- mice significantly reduced urinary albumin excretion, glomerular hyperfiltration, blood glucose levels, histological deterioration and systolic blood pressure (SBP) with decreased urinary catecholamine compared to diabetic Ca[v]2.2+/+ mice. Interestingly, diabetic heterozygous Ca[v]2.2+/- mice also decreased albuminuria, although they exhibited comparable systolic blood pressure, sympathetic nerve activity and creatinine clearance to diabetic Ca[v]2.2+/+ mice. Consistently, diabetic mice with cilnidipine, an N-/L-type calcium channel blocker, showed a reduction in albuminuria and improvement of glomerular changes compared to diabetic mice with nitrendipine. In cultured podocytes, depolarization-dependent calcium responses were decreased by ω-conotoxin, a Ca[v]2.2-specific inhibitor. Furthermore, reduction of nephrin by transforming growth factor-β (TGF-β) in podocytes was abolished with ω-conotoxin, cilnidipine or mitogen-activated protein kinase kinase inhibitor. In conclusion, Ca[v]2.2 inhibition exerts renoprotective effects against the progression of diabetic nephropathy, partly by protecting podocytes.
Rights: This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
URI: http://hdl.handle.net/2433/215697
DOI(Published Version): 10.1038/srep27192
PubMed ID: 27273361
Appears in Collections:Journal Articles

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