title: Reduced tubular cation transport in diabetes: prevented by ACE inhibition.
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.
  
  
  CONCLUSIONS
  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).
authors.affiliation: Division of Diabetic Complications, Baker Medical Research Institute, Melbourne, Victoria, Australia. mthomas@baker.edu.au
authors.forename: Merlin C
authors.initials: MC
authors.lastname: Thomas
authors.forename: Chris
authors.initials: C
authors.lastname: Tikellis
authors.forename: Wendy C
authors.initials: WC
authors.lastname: Burns
authors.forename: Vicki
authors.initials: V
authors.lastname: Thallas
authors.forename: Josephine M
authors.initials: JM
authors.lastname: Forbes
authors.forename: Zemin
authors.initials: Z
authors.lastname: Cao
authors.forename: Tanya M
authors.initials: TM
authors.lastname: Osicka
authors.forename: Leileata M
authors.initials: LM
authors.lastname: Russo
authors.forename: George
authors.initials: G
authors.lastname: Jerums
authors.forename: Hany
authors.initials: H
authors.lastname: Ghabrial
authors.forename: Mark E
authors.initials: ME
authors.lastname: Cooper
authors.forename: Phillip
authors.initials: P
authors.lastname: Kantharidis
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002412:Cations / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000378:metabolism*; D015870:Gene Expression; D007684:Kidney Tubules / Q000378:metabolism*; D008297:Male; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000378:metabolism; D027701:Organic Cation Transport Proteins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D017257:Ramipril / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012084:Renin-Angiotensin System / Q000502:physiology
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D002412:Cations; D027701:Organic Cation Transport Proteins; D012333:RNA, Messenger; D009536:Niacinamide; D017257:Ramipril; C008472:N-methylnicotinamide