Reduced Tubular Cation Transport in Diabetes: Prevented by ACE Inhibition

Kidney Int. 2003 Jun;63(6):2152-61. doi: 10.1046/j.1523-1755.2003.00006.x.

Abstract

Background: The renal clearance of organic cations is important for the homeostasis of a number of exogenous and endogenous compounds. The organic cation transporters (OCTs) situated on the basolateral surface of proximal tubular cells mediate active cation excretion. Alterations of cation transport may occur in diabetes, although the role of the OCTs has not been previously assessed.

Methods: Experimental diabetes was induced in rats with streptozotocin (55 mg/kg) and animals were randomly assigned to receive ramipril (3 mg/mL) in drinking water for 24 weeks. In a second protocol, rats were infused with angiotensin II (Ang II) at a dose of 58.3 ng/kg/min for 2 weeks via an implanted osmotic pump. Expression of the OCTs and renal clearance of the endogenous cation N-methyl-nicotinamide (NMN) was assessed.

Results: Diabetes was associated with a reduction in gene and protein expression of both OCT-1 and OCT-2 and a reduction in NMN clearance. These effects were prevented by ramipril, associated with the prevention of albuminuria and tubular injury as demonstrated by the expression of osteopontin and glutathione peroxidase 3 (GPX-3). An infusion of Ang II also reduced NMN clearance but without altering the renal expression of OCTs.

Conclusion: We hypothesize that reduced expression of OCTs in diabetes may be a marker of tubular injury. However, Ang II may also directly augment renal cation clearance independent of changes in transporter expression. Together these effects may provide additional mechanism to explain treatment-related improvements in creatinine clearance and renoprotection in diabetes following blockade of the renin-angiotensin system (RAS).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin-Converting Enzyme Inhibitors / pharmacology*
  • Animals
  • Biological Transport / drug effects
  • Cations / metabolism
  • Diabetes Mellitus, Experimental / drug therapy
  • Diabetes Mellitus, Experimental / metabolism
  • Diabetic Nephropathies / drug therapy*
  • Diabetic Nephropathies / metabolism*
  • Gene Expression
  • Kidney Tubules / metabolism*
  • Male
  • Niacinamide / analogs & derivatives*
  • Niacinamide / metabolism
  • Organic Cation Transport Proteins / genetics
  • Organic Cation Transport Proteins / metabolism
  • RNA, Messenger / analysis
  • Ramipril / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Renin-Angiotensin System / physiology

Substances

  • Angiotensin-Converting Enzyme Inhibitors
  • Cations
  • Organic Cation Transport Proteins
  • RNA, Messenger
  • Niacinamide
  • Ramipril
  • N-methylnicotinamide