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

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.

• Authors: Shoko Ohno, Hideki Yokoi, Kiyoshi Mori, Masato Kasahara, Koichiro Kuwahara, Junji Fujikura, Masaki Naito, Takashige Kuwabara, Hirotaka Imamaki, Akira Ishii, Moin A Saleem, Tomohiro Numata, Yasuo Mori, Kazuwa Nakao, Motoko Yanagita, Masashi Mukoyama
• Journal: Scientific reports (Sci Rep) Vol. 6 Pg. 27192 (06 07 2016) ISSN: 2045-2322 [Electronic] England
• PMID: 27273361 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Blood Glucose
• Cacna1b protein, mouse
• Calcium Channels, N-Type
• omega-Conotoxins

Topics

• Animals
• Blood Glucose (drug effects, metabolism)
• Blood Pressure (drug effects)
• Calcium Channels, N-Type (drug effects, genetics, metabolism)
• Cells, Cultured
• Diabetes Mellitus, Experimental
• Diabetic Nephropathies (drug therapy, metabolism, physiopathology)
• Disease Models, Animal
• Gene Knockout Techniques
• Kidney Tubules, Distal (cytology, metabolism)
• Mice
• Podocytes (cytology, metabolism)
• omega-Conotoxins (administration & dosage, pharmacology)