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.
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.
Shim
Won-Sik
WS
National Research Laboratory of Transporters, Targeted New Drug Design and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Korea.
Park
Joo-Hyun
JH
Ahn
Sun-Joo
SJ
Han
Liwei
L
Jin
Qing-Ri
QR
Li
Hong
H
Choi
Min-Koo
MK
Kim
Dae-Duk
DD
Chung
Suk-Jae
SJ
Shim
Chang-Koo
CK
D058186:Acute Kidney Injury / Q000097:blood / Q000139:chemically induced / Q000378:metabolism*; D000818:Animals; D004195:Disease Models, Animal; D015536:Down-Regulation; D007679:Kidney Medulla / Q000378:metabolism*; D008297:Male; D027701:Organic Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D000075102:Organic Cation Transporter 2; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013739:Testosterone / Q000097:blood*; D019789:Tetraethylammonium / Q000493:pharmacokinetics*; D014018:Tissue Distribution; D014502:Uranyl Nitrate
D027701:Organic Cation Transport Proteins; D000075102:Organic Cation Transporter 2; D012333:RNA, Messenger; C100590:Slc22a2 protein, rat; D014502:Uranyl Nitrate; D013739:Testosterone; D019789:Tetraethylammonium