Ablation of the N-type calcium channel ameliorates diabetic nephropathy with improved glycemic control and reduced blood pressure.
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.
Department of Nephrology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Shoko
S
Ohno
Department of Nephrology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Hideki
H
Yokoi
Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Kiyoshi
K
Mori
Institute for Clinical and Translational Science, Nara Medical University Hospital, Kashihara, Japan.
Masato
M
Kasahara
Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Koichiro
K
Kuwahara
Department of Diabetes, Endocrinology and Nutrition, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Junji
J
Fujikura
Department of Diabetes, Endocrinology and Nutrition, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Masaki
M
Naito
Department of Nephrology, Kyoto University Graduate School of Medicine, Kyoto, Japan.|Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan.
Takashige
T
Kuwabara
Department of Nephrology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Hirotaka
H
Imamaki
Department of Nephrology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Akira
A
Ishii
Children's Renal Unit, Bristol Royal Hospital for Children, University of Bristol, Bristol, UK.
Moin A
MA
Saleem
Department of Synthetic Chemistry and Biological Chemistry, Kyoto University Graduate School of Engineering, Kyoto, Japan.|Department of Physiology, Fukuoka University Graduate School of Medical Sciences, Fukuoka, Japan.
Tomohiro
T
Numata
Department of Synthetic Chemistry and Biological Chemistry, Kyoto University Graduate School of Engineering, Kyoto, Japan.
Yasuo
Y
Mori
Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Kazuwa
K
Nakao
Department of Nephrology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Motoko
M
Yanagita
Department of Nephrology, Kyoto University Graduate School of Medicine, Kyoto, Japan.|Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan.
Masashi
M
Mukoyama
D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism*; D001794:Blood Pressure / Q000187:drug effects*; D020864:Calcium Channels, N-Type / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D055786:Gene Knockout Techniques; D007686:Kidney Tubules, Distal / Q000166:cytology / Q000378:metabolism; D051379:Mice; D050199:Podocytes / Q000166:cytology / Q000378:metabolism; D020960:omega-Conotoxins / Q000008:administration & dosage* / Q000494:pharmacology
D001786:Blood Glucose; C500963:Cacna1b protein, mouse; D020864:Calcium Channels, N-Type; D020960:omega-Conotoxins