Upregulation of Rat Renal Cortical Organic Anion Transporter (OAT1 and OAT3) Expression in Response to Ischemia/Reperfusion Injury

Abstract

Background/Aims: Renal organic anion transporters (OAT1 and OAT3) localized in the basolateral membrane mediate the uptake of organic anions from the blood into proximal tubules. This study aimed to examine the effects of renal ischemia/reperfusion injury (IRI) on the expression of cortical renal OAT1 and OAT3 and the functional impact. Methods: Male rats underwent a right nephrectomy and clamping of the left renal pedicle for 50 min or sham operation, followed by reperfusion for 1, 2, 4 and 6 days. The expression of OAT1 and OAT3 was detected by RT-PCR, immunohistochemistry and Western blot analysis. Na⁺-K⁺-ATPase activity was also estimated. Results: The renal clearance of para-aminohippurate was significantly decreased on day 1 in IRI rats compared with sham-operated rats and returned to normal when the tubular injury recovered. There were significant increases in the mRNA and protein levels of OAT1 and OAT3 in renal cortex homogenates and basolateral membranes on day 1 after IRI, while on days 2 and 4 after IRI, the renal expression of OAT1 and OAT3 decreased gradually but was still significantly higher than that of the sham-operated rats. The Na⁺-K⁺-ATPase activity in renal cortex homogenates decreased significantly on day 1 after IRI but gradually increased on days 2, 4 and 6. Conclusions: Renal para-aminohippurate clearance was depressed in response to IRI; however, the expressions of renal cortex OAT1 and OAT3 were significantly elevated in the early stage of IRI which may have substantial impact on renal excretion of some drugs and toxic compounds.

Seventy-Five Percent Nephrectomy and the Disposition of Inorganic Mercury in 2,3-Dimercaptopropanesulfonic Acid-Treated Rats Lacking Functional Multidrug-Resistance Protein 2

“…We hypothesize that enhanced expression of these two transporters provides a more efficient secretory route for the elimination of Hg 2ϩ and other xenobiotics in hypertrophied proximal tubular epithelial cells, particularly those lining the pars recta where tubular secretion is most prominent. Additional findings from Zhang et al (2008) support our current molecular findings. They demonstrated that expression of OAT1 and OAT3 proteins was enhanced in proximal tubular cells in an ischemic/reperfusion rat model in which the animals underwent a right-sided uninephrectomy followed by compression of the left renal pedicle for 50 min.…”

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

“…Therefore, renal injury may have reduced indoxyl sulfate secretion through OAT downregulation. In contrast to these results, others have found that, although PAH renal clearance was blunted, rOat1 and rOat3 mRNA and protein levels were increased in both the renal cortex and basolateral membrane despite using a similar duration of ischemia ($50 min) and reperfusion (24 h) to the studies above [116]. A major difference in the latter study was the use of a unilateral nephrectomy with clamping of the opposite renal artery, compared with the former two studies that employed bilateral renal artery clamping without nephrectomy.…”

Expression of xenobiotic transporters in the human renal proximal tubule cell line RPTEC/TERT1

“…OCT2 (SLC22A2) transports cisplatin (Ciarimboli et al, 2005;Ludwig et al, 2004;Tanihara et al, 2009), cimetidine, ifosfamide (Ciarimboli et al, 2011), ß-blockers, fluoroquinolones (Zhang et al, 2008), and amantadine. OCT3 (SLC22A3) transports clonidine, ketamine, and fluoxetine and OCTN2 (SLC22A5) transports cephalosporin antibiotics (De Broe and Roch-Ramel, 2008;Koepsell et al, 2007).…”