title: A role for the organic anion transporter OAT3 in renal creatinine secretion in mice.
abstract: Tubular secretion of the organic cation, creatinine, limits its value as a marker of glomerular filtration rate (GFR) but the molecular determinants of this pathway are unclear. The organic anion transporters, OAT1 and OAT3, are expressed on the basolateral membrane of the proximal tubule and transport organic anions but also neutral compounds and cations. Here, we demonstrate specific uptake of creatinine into mouse mOat1- and mOat3-microinjected Xenopus laevis oocytes at a concentration of 10 μM (i.e., similar to physiological plasma levels), which was inhibited by both probenecid and cimetidine, prototypical competitive inhibitors of organic anion and cation transporters, respectively. Renal creatinine clearance was consistently greater than inulin clearance (as a measure of GFR) in wild-type (WT) mice but not in mice lacking OAT1 (Oat1-/-) and OAT3 (Oat3-/-). WT mice presented renal creatinine net secretion (0.23 ± 0.03 μg/min) which represented 45 ± 6% of total renal creatinine excretion. Mean values for renal creatinine net secretion and renal creatinine secretion fraction were not different from zero in Oat1-/- (-0.03 ± 0.10 μg/min; -3 ± 18%) and Oat3-/- (0.01 ± 0.06 μg/min; -6 ± 19%), with greater variability in Oat1-/-. Expression of OAT3 protein in the renal membranes of Oat1-/- mice was reduced to ∼6% of WT levels, and that of OAT1 in Oat3-/- mice to ∼60%, possibly as a consequence of the genes for Oat1 and Oat3 having adjacent chromosomal locations. Plasma creatinine concentrations of Oat3-/- were elevated in clearance studies under anesthesia but not following brief isoflurane anesthesia, indicating that the former condition enhanced the quantitative contribution of OAT3 for renal creatinine secretion. The results are consistent with a contribution of OAT3 and possibly OAT1 to renal creatinine secretion in mice.
authors.affiliation: Depts. of Medicine and Pharmacology, Univ. of California San Diego and VASDHCS, 3350 La Jolla Village Dr. (9151 San Diego, CA 92161, USA. vvallon@ucsd.edu
authors.forename: Volker
authors.initials: V
authors.lastname: Vallon
authors.forename: Satish A
authors.initials: SA
authors.lastname: Eraly
authors.forename: Satish Ramachandra
authors.initials: SR
authors.lastname: Rao
authors.forename: Maria
authors.initials: M
authors.lastname: Gerasimova
authors.forename: Michael
authors.initials: M
authors.lastname: Rose
authors.forename: Megha
authors.initials: M
authors.lastname: Nagle
authors.forename: Naohiko
authors.initials: N
authors.lastname: Anzai
authors.forename: Travis
authors.initials: T
authors.lastname: Smith
authors.forename: Kumar
authors.initials: K
authors.lastname: Sharma
authors.forename: Sanjay K
authors.initials: SK
authors.lastname: Nigam
authors.forename: Timo
authors.initials: T
authors.lastname: Rieg
mesh_terms: D000818:Animals; D002927:Cimetidine / Q000494:pharmacology; D003404:Creatinine / Q000097:blood / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005919:Glomerular Filtration Rate / Q000502:physiology; D007668:Kidney / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009865:Oocytes / Q000502:physiology; D027362:Organic Anion Transport Protein 1 / Q000235:genetics / Q000378:metabolism; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics* / Q000378:metabolism*; D027701:Organic Cation Transport Proteins / Q000235:genetics / Q000378:metabolism; D000075102:Organic Cation Transporter 2; D011339:Probenecid / Q000494:pharmacology; D014528:Uricosuric Agents / Q000494:pharmacology; D014982:Xenopus laevis
chemical_list: D004791:Enzyme Inhibitors; D008565:Membrane Proteins; D027362:Organic Anion Transport Protein 1; D029362:Organic Anion Transporters, Sodium-Independent; D027701:Organic Cation Transport Proteins; D000075102:Organic Cation Transporter 2; C491012:Slc22a2 protein, mouse; C105033:Slc22a6 protein, mouse; D014528:Uricosuric Agents; C114338:organic anion transport protein 3; D002927:Cimetidine; D003404:Creatinine; D011339:Probenecid