A role for the organic anion transporter OAT3 in renal creatinine secretion in mice

Abstract

<jats:p>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.</jats:p>

Identification and Quantitative Assessment of Uremic Solutes as Inhibitors of Renal Organic Anion Transporters, OAT1 and OAT3

“…OAT3 was reported to contribute to the elimination of creatinine in mice. 37,38 There are also two publications showing that human OAT3 takes up creatinine. 39,40 In contrast to the previous studies, Lepist et al reported that creatinine was not transported by human OAT1 or OAT3.…”

The Kidney and Uremic Toxin Removal: Glomerulus or Tubule?

“…Surprisingly, the fractional creatinine secretion was lower in female mice as compared with males, which correlated to the relative mRNA expression levels of Oat1, further supporting a role for organic anion transporters in renal creatinine secretion. Recently, Vallon et al 75 investigated this further using Oat1-and Oat3-deficient mice and confirmed a role for the organic anion transporters in creatinine secretion with a more pronounced role of Oat3. In contrast, creatinine inhibited organic cation transport in freshly isolated proximal tubules from wild-type mice but not in Oct1/2-deficient mice.…”

Handling of Drugs, Metabolites, and Uremic Toxins by Kidney Proximal Tubule Drug Transporters

“…Drugs such as cimetidine and trimethoprim are examples. OATs, while mainly transporters of organic anions, can also transport some organic cations, including creatinine (32,33). In addition, newer agents, such as the integrase inhibitor dolutegravir and the novel pharmacoenhancer cobicistat, also block creatinine excretion (34,35).…”

“…In addition, newer agents, such as the integrase inhibitor dolutegravir and the novel pharmacoenhancer cobicistat, also block creatinine excretion (34,35). This effect appears to be largely from drug-metabolite interactions due to competition for OCTs, MATEs, and possibly OATs (29,(32)(33)(34)(35).…”