| Authors |
Vallon V, Eraly SA, Rao SR, Gerasimova M, Rose M, Nagle M, Anzai N, Smith T,
Sharma K, Nigam SK, Rieg T
|
| Submitted By |
Kumar Sharma on 8/1/2012 |
| Status |
Published |
| Journal |
American journal of physiology. Renal physiology |
| Year |
2012 |
| Date Published |
5/1/2012 |
| Volume : Pages |
302 : F1293 - F1299 |
| PubMed Reference |
|
| 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 碌M (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 卤 0.03 碌g/min) which represented 45 卤 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 卤
0.10 碌g/min; -3 卤 18%) and Oat3-/- (0.01 卤 0.06 碌g/min; -6 卤 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.
|
|
|