Reduced tubular cation transport in diabetes: Prevented by ACE inhibition

Merlin C. Thomas, Chris Tikellis, Wendy C. Burns, Vicki Thallas, Josephine M. Forbes, Zemin Cao, Tanya M. Osicka, Leileata M. Russo, George Jerums, Hany Ghabrial, Mark E. Cooper, Phillip Kantharidis

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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).

Original languageEnglish
Pages (from-to)2152-2161
Number of pages10
JournalKidney International
Volume63
Issue number6
DOIs
Publication statusPublished - 1 Jun 2003
Externally publishedYes

Keywords

  • Cation
  • Diabetes
  • Proximal transport

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