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Sci Rep. 2016 Jun 7;6:27192. doi: 10.1038/srep27192.

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

Author information

1
Department of Nephrology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
2
Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan.
3
Institute for Clinical and Translational Science, Nara Medical University Hospital, Kashihara, Japan.
4
Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
5
Department of Diabetes, Endocrinology and Nutrition, Kyoto University Graduate School of Medicine, Kyoto, Japan.
6
Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan.
7
Children's Renal Unit, Bristol Royal Hospital for Children, University of Bristol, Bristol, UK.
8
Department of Synthetic Chemistry and Biological Chemistry, Kyoto University Graduate School of Engineering, Kyoto, Japan.
9
Department of Physiology, Fukuoka University Graduate School of Medical Sciences, Fukuoka, Japan.

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, Cav2.2, in diabetic nephropathy, however, remains to be clarified. To examine functional roles, we mated Cav2.2(-/-) mice with db/db (diabetic) mice on the C57BLKS background. Cav2.2 was localized in glomeruli including podocytes and in distal tubular cells. Diabetic Cav2.2(-/-) 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 Cav2.2(+/+) mice. Interestingly, diabetic heterozygous Cav2.2(+/-) mice also decreased albuminuria, although they exhibited comparable systolic blood pressure, sympathetic nerve activity and creatinine clearance to diabetic Cav2.2(+/+) 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 Cav2.2-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, Cav2.2 inhibition exerts renoprotective effects against the progression of diabetic nephropathy, partly by protecting podocytes.

PMID:
27273361
PMCID:
PMC4895143
DOI:
10.1038/srep27192
[Indexed for MEDLINE]
Free PMC Article

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