Ion Channels – Membrane Transport – Integrative Physiology
Kidney International (2002) 62, 514–524; doi:10.1046/j.1523-1755.2002.00464.x
Down-regulation of rat organic cation transporter rOCT2 by 5/6 nephrectomy
Lin Ji, Satohiro Masuda, Hideyuki Saito and Ken-Ichi Inui
Department of Pharmacy, Kyoto University Hospital, Faculty of Medicine, Kyoto, Japan
Correspondence: Professor Ken-ichi Inui, Ph.D., Department of Pharmacy, Kyoto University Hospital, Sakyo-ku, Kyoto 606-8507, Japan. E-mail: inui@kuhp.kyoto-u.ac.jp
Received 2 October 2001; Revised 5 February 2002; Accepted 8 March 2002.
Abstract
Down-regulation of rat organic cation transporter rOCT2 by 5/6 nephrectomy.
Background
In rat kidneys, the organic ion transporters rOCT1, rOCT2, rOAT1 and rOAT3 are considered to mediate the basolateral uptake of various ionic compounds. However, their changes in chronic renal failure (CRF) are poorly understood. The present study examined the renal handling of organic ions and the expression of these transporters under CRF.
Methods
5/6 Nephrectomized rats were used as the animal model of CRF. Renal handlings of cimetidine and paraaminohippuric acid (PAH) were examined by in vivo experiments. rOAT1, rOAT3, rOCT1 and rOCT2 expressions were determined by Western blotting.
Results
The tubular secretion rates of both PAH and cimetidine were markedly decreased in CRF rats. Although the distribution rates of PAH into the kidney cortex and medulla, and of cimetidine into the kidney cortex were maintained, the distribution rate of cimetidine into the kidney medulla was significantly decreased in CRF rats. The expression level of the rOCT2 protein was markedly depressed in CRF rats, but those of rOCT1, rOAT1 and rOAT3 were maintained. In addition, the plasma concentration of testosterone, a regulator of rOCT2 expression, was significantly reduced by CRF. Both the renal clearance of cimetidine and rOCT2 expression were recovered by the exogenous administration of testosterone in CRF rats.
Conclusions
The levels of urinary excretion of cationic drugs, especially substrates for rOCT2, were reduced under CRF partly due to the reduced expression of rOCT2, and the lowered plasma level of testosterone was suggested to be responsible for the depressed rOCT2 expression in CRF.
Keywords:
cimetidine, p-aminohippuric acid, chronic renal failure, renal clearance, organic anion transporter, testosterone, remnant kidney
Abbreviations:
AUC, area under the plasma concentration-time curve; BUN, blood urea nitrogen; Cpss, steady state plasma concentration; Cren, renal clearance; Cr.f, renal clearance of unbound PAH or cimetidine; CRF, chronic renal failure; Ctot, total plasma clearance; ELISA, enzyme-linked immunosorbent assay; fu, unbound fraction; GFR, glomerular filtration rate; HPLC, high performance liquid chromatography; Kp, tissue to plasma concentration ratio; Nx, nephrectomy; OAT, organic anion transporter; OCT, organic cation transporter; PAH, paraaminohippurate; T, with (+) or (-) without testosterone enathate
