Testosterone‐Independent Down‐Regulation of Oct2 in the Kidney Medulla from a Uranyl Nitrate‐Induced Rat Model of Acute Renal Failure: Effects on Distribution of a Model Organic Cation, Tetraethylammonium

Abstract

Although acute renal failure (ARF) has been an area of extensive research in recent decades, our understanding of ARF is far from complete. Organic cations (OCs) are primarily excreted via vectorial transport by various renal organic cation transporters (OCTs). It is reasonable to assume that ARF may alter the expression profiles of these transporters. In a rat ARF model, induction of ARF by uranyl nitrate (UN) treatment significantly decreased the levels of Oct2 (slc22a2) mRNA and protein in the kidney medulla. mRNA expression of the other OCTs was not appreciably altered. The plasma level of testosterone, a well‐known regulator of Oct2, was not changed, suggesting that the Oct2 down‐regulation is testosterone‐independent. The effect of reduced Oct2 expression on the distribution of a model OC, tetraethylammonium (TEA), in various rat tissues including kidney cortex and kidney medulla was investigated during steady state plasma TEA concentrations. The steady state tissue‐to‐plasma (T/P) TEA ratio was decreased in the kidney medulla (approximately 15‐fold) during ARF. These results indicate that, in a rat model of ARF, reduced Oct2 expression in the kidney medulla results in decreased distribution of TEA to the kidney medulla, thereby reducing renal clearance of TEA in UN‐ARF rats. © 2008 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:739–747, 2009