Background: Urinary tract obstruction is a common cause of renal failure. In this study, we evaluated the time course of P-aminohippurate (PAH) renal excretion and the cortical expression of organic anion transporters (Oat1 and Oat3) at 1 (BUO-1), 2 (BUO-2) and 7 (BUO-7) days after release of 24-hour bilateral ureteral obstruction (BUO) in the rat. Methods: Conventional clearance technique, differential centrifugation, semiquantitative immunoblotting and immunohistochemical techniques have been employed. Results: These studies showed that Oat1 and Oat3 in basolateral membranes were downregulated both at BUO-1 and BUO-2. Concomitantly, the rats developed a reduction in PAH renal elimination. In contrast, total recovery in PAH renal excretion and in the expression of Oat1 and Oat3 were observed at BUO-7, as compared with the sham group. A direct correlation was observed between the secretory clearance of PAH and Oat1 (r2 = 0.88) and Oat3 (r2 = 0.83) expression in basolateral membranes. Conclusion: These results indicate that the differential expression of organic anion transporters is one of the main molecular mechanisms contributing to the organic anion excretion modifications observed during the time course of obstructive nephropathy. This study provides evidence regarding the importance of adjusting the dose regimens of negatively charged drugs during the different time phases of this pathology.

1.
Klahr S: Obstructive uropathy; in Seldin DW, Giebisch G (eds): The Kidney. Physiology and Pathophysiology. Philadelphia, Lippincott Williams & Wilkins, 2000, pp 2473–2512.
2.
Curhan GC, Zeidel ML: Urinary tract obstruction; in Brenner BM, Rector FC (eds): The Kidney. Pennsylvania, Saunders, 1996, pp 1936–1958.
3.
Klahr S: Obstructive nephropathy. Intern Med 2000;39:355–361.
4.
Chevalier RL: Molecular and cellular pathophysiology of obstructive nephropathy. Pediatr Nephrol 1999;13:612–619.
5.
Anzai N, Kanai Y, Endou H: Organic anion transporter family: current knowledge. J Pharmacol Sci 2006;100:411–426.
6.
Wright SH, Dantzler WH: Molecular and cellular physiology of renal organic cation and anion transport. Physiol Rev 2004;84:987–1049.
7.
Rizwan AN, Burckhardt G: Organic anion transporters of the SLC22 family: biopharmaceutical, physiological, and pathological roles. Pharm Res 2007;24:450–470.
8.
Sweet DH, Wolff NA, Pritchard JB: Expression cloning and characterization of ROAT1. The basolateral organic anion transporter in rat kidney. J Biol Chem 1997;272:30088–30095.
9.
Kojima R, Sekine T, Kawachi M, Cha SH, Suzuki I, Endou H: Immunolocalization of multispecific organic anion transporters, OAT1, OAT2, and OAT3, in rat kidney. J Am Soc Nephrol 2002;13:848–857.
10.
Sekine T, Watanabe N, Hosoyamada, Kanai Y, Endou H: Expression cloning and characterization of a novel multispecific organic anion transporter. J Biol Chem 1997;272:18526–18529.
11.
Cha SH, Sekine T, Fukushima J, Kanai Y, Kobayashi Y, Goya T, Endou H: Identification and characterization of human organic anion transporter 3 expressing predominantly in the kidney. Mol Pharmacol 2001;59:1277–1286.
12.
Sweet DH, Chan LMS, Walden R, Yang XP, Miller DS, Pritchard JC: Organic anion transporter 3 [Slc22a8] is a dicarboxylate exchanger indirectly coupled to the Na+ gradient. Am J Physiol 2003;284:F763–F769.
13.
Villar SR, Brandoni A, Quaglia NB, Torres AM: Renal elimination of organic anions in rats with bilateral ureteral obstruction. Biochim Biophys Acta 2004;1688:204–209.
14.
Villar SR, Brandoni A, Anzai N, Endou H, Torres AM: Altered expression of rat renal cortical OAT1 and OAT3 in response to bilateral ureteral obstruction. Kidney Int 2006;68:2704–2713.
15.
Torres AM, Rodriguez J, Elias MM: Vulnerability of the ascending limb to glutathione depletion in rat kidney: effects of diuretics and indomethacin. J Pharmacol Exp Ther 1989;250:247–253.
16.
Cerrutti JA, Quaglia NB, Torres AM: Characterization of the mechanisms involved in the gender differences in P-aminohippurate renal elimination in rats. Can J Physiol Pharmacol 2001;79:805–813.
17.
Brandoni A, Villar SR, Torres AM: Gender-related differences in the pharmacodynamics of furosemide in rats. Pharmacology 2004;70:107–112.
18.
Quaglia NB, Brandoni A, Villar S, Torres AM: Haemodynamic and tubular renal dysfunction in rats with sustained arterial calcinosis. Clin Exp Pharmacol Physiol 2004;31:231–236.
19.
Waugh WH, Beall PT: Simplified measurement of PAH and other arylamines in plasma and urine. Kidney Int 1974;5:429–432.
20.
Roe HH, Epstein JH, Goldstein NP: A photometric method for determination of inulin in plasma and urine. J Biol Chem 1949;178:839–844.
21.
Marples D, Knepper MA, Christensen EI, Nielsen S: Redistribution of aquaporin-2 water channels induced by vasopressin in rat kidney inner medullary collecting duct. Am J Physiol 1995;269:C655–C664.
22.
Graham J: Isolation of subcellular organelles and membranes; in Rickwood IRL (ed): Centrifugation. A Practical Approach. Oxford, Oxford University Press. 1984, pp 161–182.
23.
Sedmak JJ, Grossberg SE: A rapid, sensitive and versatile assay for protein using Coomassie brilliant blue G250. Anal Biochem 1977;79:544–552.
24.
Jensen RE, Berndt WO: Epinephrine and norephinephrine enhance P-aminohippurate transport into basolateral membrane vesicles. J Pharmacol Exp Ther 1988;244:543–549.
25.
Cerrutti JA, Brandoni A, Quaglia NB, Torres AM: Sex differences in P-aminohippuric acid transport in rat kidney: role of membrane fluidity and expression of OAT1. Mol Cell Biochem 2002;233:175–179.
26.
Brandoni A, Villar SR, Picena JC, Anzai N, Endou H, Torres AM: Expression of rat renal cortical OAT1 and OAT3 in response to acute biliary obstruction. Hepatology 2006;43:1092–1100.
27.
Brandoni A, Anzai N, Kanai Y, Endou H, Torres AM: Renal elimination of P-aminohippurate (PAH) in response to three days of biliary obstruction in the rat. The role of OAT1 and OAT3. Biochim Biophys Acta 2006;1762:673–682.
28.
Shah V, Cao S, Hendrickson H, Yao J, Katusic ZS: Regulation of hepatic eNOS by caveolin and calmodulin after bile duct ligation in rats. Am J Physiol 2001;G280:G1209–G1216.
29.
Schoner W, Von Ilberg C, Kramer R, Seubert W: On the mechanism of Na+ and K+ stimulation hydrolysis of adenosine triphosphate. Eur J Biochem 1967;1:334–343.
30.
Glenny RW: Manual for Using Fluorescent Microspheres to Measure Regional Organ Perfusion. Seattle, University of Washington, 1996.
31.
Wen JG, Frokiaer J, Jorgenen TM, Djurhuus JC: Obstructive nephropathy: an update of the experimental research. Urol Res 1999;27:29–39.
32.
Van Aubel RAMH, Masereeuw R, Russel FGM: Molecular pharmacology of renal organic anion transporters. Am J Physiol 2000;279:F216–F232.
33.
Eraly SA, Vallon V, Vaughn DA, Gangoiti JA, Richter K, Nagle M, Monte JC, Rieg T, Truong DM, Long JM, Barshop BA, Kaler G, Nigam SK: Decrease renal organic secretion and plasma accumulation of endogenous organic anions in OAT1 knock-out mice. J Biol Chem 2006;281:5072–5083.
34.
Vallon V, Rieg T, Young Ahn S, Wu W, Eraly SA, Nigam SK: Overlapping in vitro and in vivo specificities of the organic anion transporters OAT1 and OAT3 for loop and thiazide diuretics. Am J Physiol 2008;294:F867–F873.
35.
Wolff NA, Thies K, Kuhnke N, Reid G, Friedrich B, Lang F, Burckhardt G: Protein kinase C activation downregulates human organic anion transporter 1-mediated transport through carrier internalization. J Am Soc Nephrol 2003;14:1959–1968.
36.
Takeda M, Sekine T, Endou H: Regulation by protein kinase C of organic anion transport driven by rat organic anion transporter 3 (rOAT3). Life Sci 2000;67:1087–1083.
37.
Karim Z, Defontaine N, Paillard M, Poggioli J: Protein kinase C isoforms in rat kidney proximal tubule: acute effect of angiotensin II. Am J Physiol 1995;269:F134–F140.
38.
Nagai J, Yano I, Hashimoto H, Takano M, Inui K: Inhibition of PAH transport by parathyroid hormone in OK cells: involvement of protein kinase C pathway. Am J Physiol 1997;273:F674–F679.
39.
Klahr S, Morrissey J: Obstructive nephropathy and renal fibrosis. Am J Physiol 2004;286:F861–F783.
40.
Enomoto A, Takeda M, Tojo A, Sekine T, Cha SH, Khamdang S, Takayama F, Aoyama I, Nakamura S, Endou H, Niwa T: Role of organic anion transporters in the tubular transport of indoxyl sulfate and the induction of its nephrotoxicity. J Am Soc Nephrol 2002;13:1711–1720.
41.
Deguchi T, Ohtsuki S, Otagiri M, Takanaga H, Asaba H, Mori S, Terasa T: Major role of organic anion transporter 3 in the transport of indoxyl sulfate in the kidney. Kidney Int 2002;61:1760–1768.
42.
Sun H, Frassetto L, Benet LZ: Effects of renal failure on drug transport and metabolism. Pharmacol Ther 2006;109:1–11.
43.
Niwa T, Ise M: Indoxyl sulfate, a circulating uremic toxin, stimulates the progression of glomerular sclerosis. J Lab Clin Med 1994;124:96–104.
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