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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

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