Downregulation of organic anion transporters OAT1 and OAT3 correlates with impaired secretion ofpara-aminohippurate after ischemic acute renal failure in rats

Abstract

M. Downregulation of organic anion transporters OAT1 and OAT3 correlates with impaired secretion of para-aminohippurate after ischemic acute renal failure in rats. Am J Physiol Renal Physiol 292: F1599 -F1605, 2007. First published January 23, 2007; doi:10.1152/ajprenal.00473.2006.-Ischemic acute renal failure (iARF) was described to reduce renal extraction of the organic anion para-aminohippurate (PAH) in humans. The rate-limiting step of renal organic anion secretion is its basolateral uptake into proximal tubular cells. This process is mediated by the organic anion transporters OAT1 and OAT3, which both have a broad spectrum of substrates including a variety of pharmaceutics and toxins. Using a rat model of iARF, we investigated whether impairing the secretion of the organic anion PAH might be associated with downregulation of OAT1 or OAT3. Inulin and PAH clearance was determined starting from 6 up to 336 h after ischemiareperfusion (I/R) injury. Net secretion of PAH was calculated and OAT1 as well as OAT3 expression was analyzed by RT-PCR and Western blotting. Inulin and PAH clearance along with PAH net secretion were initially diminished after I/R injury with a gradual recovery during follow-up. This initial impairment after iARF was accompanied by decreased mRNA and protein levels of OAT1 and OAT3 in clamped animals compared with sham-operated controls. In correlation to the improvement of kidney function, both mRNA and protein levels of OAT1 and OAT3 were upregulated during the follow-up. Thus decreased expression of OAT1 and OAT3 is sufficient to explain the decline of PAH secretion after iARF. As a result, this may have substantial impact on excretion kinetics and half-life of organic anions. As a consequence, the biological effects of a variety of organic anions may be affected after iARF. organic anion transporter 1; organic anion transporter 3; proximal tubule; basolateral uptake; renal plasma flow; glomerular filtration; inulin; clearance; PAH net secretion THE ORGANIC ANION TRANSPORT system of the renal proximal tubule plays a crucial role in the excretion of a variety of potentially toxic compounds (22,35). This system consists of organic anion exchangers located at the basolateral membrane and a less well-characterized transport step at the apical membrane (8). The classical basolateral organic anion exchanger is the terminal step in a tertiary active transport system, dependent on an inward-directed Na ϩ gradient to drive the uptake of ␣-ketoglutarate (␣KG), which is then exchanged for organic anions (7,11,23). It has been shown that OAT1 represents characteristics of the basolateral, polyspecific transporter for organic anions (30), which had been functionally described since substantial time (23). Recently, new evidence has indicated that OAT3 (16), which is also located in the basolateral renal proximal tubular membrane, works as an exchanger for organic anions and dicarboxylates, too (32). Moreover, additional homologs have been cloned and were called OAT2 (28), OAT4 (4), OAT5 (40), and OAT6...

Organic anion transporters: discovery, pharmacology, regulation and roles in pathophysiology

“…No other studies have assessed such post-renal obstruction with regard to OAT expression; however, investigations have evaluated the effects of ischemia-reperfusion injury on renal OAT expression/function. In two such studies, it was reported that ischemia-reperfusion injury decreased mRNA and protein expression of both rOat1 and rOat3 [111,112]. Supporting this finding, either PAH clearance was reduced [111], or indoxyl sulfate serum levels were increased with a concomitant decrease in basolateral transport of PAH and estone sulfate [112].…”

“…In two such studies, it was reported that ischemia-reperfusion injury decreased mRNA and protein expression of both rOat1 and rOat3 [111,112]. Supporting this finding, either PAH clearance was reduced [111], or indoxyl sulfate serum levels were increased with a concomitant decrease in basolateral transport of PAH and estone sulfate [112]. Indoxyl sulfate is a known OAT substrate and uremic toxin.…”

“…This is one plausible explanation for the decrease in renal organic anion transport observed after renal damage (e.g. ischemia-reperfusion injury) [111,112].…”

The Kidney and Uremic Toxin Removal: Glomerulus or Tubule?

“…25,26 Similarly, decreased human (h)OAT1, or rOat1 and rOat3, protein expression was observed in acute renal failure patients or animals with experimentally induced acute renal failure. [27][28][29][30] Renal proximal tubule cell loss owing to injury is likely a major contributing factor to this decrease in total protein expression level.…”

Post-Transcriptional Regulation of Breast Cancer Resistance Protein after Intestinal Ischemia-Reperfusion

“…5,6) It has been shown that the expression of transporters was altered in the organ after I/R. [7][8][9][10] I/R can occur in many organs, including intestine, liver and kidney. The intestine, liver and kidney play a principal role in the absorption and excretion of a wide variety of xenobiotics, including drugs and toxins, as well as endogenous compounds.…”