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Ablation of the N-type calcium channel ameliorates diabetic nephropathy with
improved glycemic control and reduced blood pressure
#MMPMID27273361
Ohno S
; Yokoi H
; Mori K
; Kasahara M
; Kuwahara K
; Fujikura J
; Naito M
; Kuwabara T
; Imamaki H
; Ishii A
; Saleem MA
; Numata T
; Mori Y
; Nakao K
; Yanagita M
; Mukoyama M
Sci Rep
2016[Jun]; 6
(?): 27192
PMID27273361
show ga
Pharmacological blockade of the N- and L-type calcium channel lessens renal
injury in kidney disease patients. The significance of specific blockade of ?1
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 ?-conotoxin, a Cav2.2-specific inhibitor.
Furthermore, reduction of nephrin by transforming growth factor-? (TGF-?) in
podocytes was abolished with ?-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.
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