Journal Article Ablation of the N-type calcium channel ameliorates diabetic nephropathy with improved glycemic control and reduced blood pressure

Ohno, Shoko  ,  Yokoi, Hideki  ,  Mori, Kiyoshi  ,  Kasahara, Masato  ,  Kuwahara, Koichiro  ,  Fujikura, Junji  ,  Naito, Masaki  ,  Kuwabara, Takashige  ,  Imamaki, Hirotaka  ,  Ishii, Akira  ,  Saleem, Moin A.  ,  Numata, Tomohiro  ,  Mori, Yasuo  ,  Nakao, Kazuwa  ,  Yanagita, Motoko  ,  Mukoyama, Masashi

62016-06-07 , Nature Publishing Group
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.

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