Postnatal development of sex differences in renal tubular transport of p-aminohippurate (PAH) in rats

Bräunlich, H; Meinig, T.; Grosch, U.

doi:10.1016/s0940-2993(11)80414-8

Cited by 23 publications

(17 citation statements)

References 13 publications

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“…Administration of estrone (structurally, estradiol is a hydroxyl, whereas estrone is a ketone) to intact male rats also markedly reduces PAH accumulation into renal slices, whereas estrone treatment of females reduces PAH accumulation to a lesser extent (Huang and McIntosh, 1955). Testosterone administration to female rats increases PAH accumulation by renal slices but has no effect on males (Huang and McIntosh, 1955;Braunlich et al, 1993). Because transport in renal slices reflects basolateral uptake, these data examining PAH transport seem correlated with sex differences in Oat1 mRNA and protein expression.…”

Section: Discussionmentioning

confidence: 85%

Sex Differences in the mRNA, Protein, and Functional Expression of Organic Anion Transporter (Oat) 1, Oat3, and Organic Cation Transporter (Oct) 2 in Rabbit Renal Proximal Tubules

Groves

Suhre

Cherrington

et al. 2005

J Pharmacol Exp Ther

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Sex differences in transport of the organic anion (OA) substrate p-aminohippurate (PAH) and the organic cation (OC) substrate tetraethylammonium (TEA) have been recognized for some time. In the rat kidney, androgens up-regulate and estrogens down-regulate PAH and TEA transport, which correlate with similar changes in mRNA and protein expression for the renal basolateral membrane transporters organic anion transporter (Oat) 1 and organic cation transporter (Oct) 2. However, these sex differences are not readily demonstrated in other species. The present study characterizes the kinetics of basolateral membrane PAH, estrone sulfate (ES), and TEA uptake in renal proximal tubule (RPT) suspensions isolated from female and male rabbits to compare functional expression of transport with mRNA and protein expression for rbOat1, rbOat3, and rbOct2. Although rbOat1-rbOat3 mRNA expression exhibited developmental differences, no sex differences in mRNA levels were observed. Oat1 and Oat3 protein expression in RPT suspensions also was similar between adult female and male rabbits. In contrast, rbOct1 and rbOct2 mRNA levels did not show developmental differences, but rbOct2 mRNA expression was greater in adult male than female rabbits. However, the sex difference in rbOct2 mRNA level did not translate to rbOct2 protein expression. Importantly, functional expression of Oat1, Oat3, and Oct2 transport as measured by kinetics (J max and K t ) of PAH, ES, and TEA uptake was similar between adult male and female rabbits, and correlated with rbOat1, rbOat3, and rbOct2 protein expression. Thus, unlike rodents, rabbit renal OA and OC transport does not exhibit sex differences, pointing to the need for caution in extrapolating transport-related sex differences between species.

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Section: Discussionmentioning

confidence: 85%

Sex Differences in the mRNA, Protein, and Functional Expression of Organic Anion Transporter (Oat) 1, Oat3, and Organic Cation Transporter (Oct) 2 in Rabbit Renal Proximal Tubules

Groves

Suhre

Cherrington

et al. 2005

J Pharmacol Exp Ther

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“…Gonadectomy of male rats reduced kidney PAH transport, which was restored by testosterone administration (Kleinman et al, 1966;Bräunlich et al, 1993). However, PAH transport was not affected by ovariectomy of female rats or estradiol administration to male rats (Kleinman et al, 1966;Bräunlich et al, 1993). Thus, estrogens did not influence the organic anion transport processes of the kidney.…”

Section: Discussionmentioning

confidence: 92%

“…Male rat kidneys reportedly accumulate PAH at a greater rate than female rat kidneys (Huang and McIntosh, 1955;Kleinman et al, 1966;Bowman and Hook, 1972). Gonadectomy of male rats reduced kidney PAH transport, which was restored by testosterone administration (Kleinman et al, 1966;Bräunlich et al, 1993). However, PAH transport was not affected by ovariectomy of female rats or estradiol administration to male rats (Kleinman et al, 1966;Bräunlich et al, 1993).…”

Section: Discussionmentioning

confidence: 98%

“…Moreover, male rat kidneys transport para-aminohippurate (PAH), an anion commonly used to study active transport in kidney, at greater rates than female rat kidneys, both in vivo and in vitro (Kleinman et al, 1966). Kleinman et al (1966) and Bräunlich et al (1993), respectively, determined that testosterone elevated PAH transport by male kidney, and estrogen had no role in gender-divergent PAH transport. Testosterone was also shown to increase expression of oatp1 in kidney (Lu et al, 1996).…”

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confidence: 99%

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Endocrine Regulation of Rat Organic Anion Transporters

Buist¹,

Cherrington²,

Klaassen³

2003

Drug Metab Dispos

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This article is available online at http://dmd.aspetjournals.org ABSTRACT:Messenger RNA levels of rat organic anion transporter 1 (Oat1; Slc22a6) and Oat2 (Slc22a7) in kidney and Oat3 (Slc22a8) in liver are gender-predominant. Oat1 and Oat3 are male-predominant, whereas Oat2 is female-predominant. Gonadectomized and hypophysectomized (HX) rats were studied to determine whether sex steroids and/or growth hormone (GH) are responsible for these gender-divergent patterns. GH was administered to HX rats by two daily injections (simulating male secretion) or continuous infusion (simulating female secretion). Oat1 mRNA levels, normally higher in male than female kidney, were lowered by gonadectomy and HX in male rats, but not in females. Additionally, GH injections or infusion did not alter Oat1 levels in HX rats. Oat2 mRNA levels, typically much higher in female than in male kidney, were unaffected by gonadectomy. However, HX dramatically decreased Oat2 in female kidney without altering male levels. GH administered by continuous infusion increased Oat2 in kidneys of both HX male and female rats, whereas injections had no affect. Gonadectomy reduced Oat3 mRNA levels in male livers without affecting levels in female livers. In contrast, HX decreased male and elevated female Oat3 mRNA. GH injections did not significantly change Oat3 mRNA levels in HX rats, but infusion decreased Oat3 mRNA in liver. In conclusion, androgens, but not GH, are responsible for the Oat1 mRNA gender difference in kidney; the female GH secretion pattern is responsible for the Oat2 mRNA gender difference in kidney; and both androgens and the female GH secretion pattern are responsible for the Oat3 mRNA gender difference in liver.Metabolism and excretion both determine elimination of endogenous and exogenous compounds. Liver is the primary site of metabolism, and liver and kidney are important organs in the process of excretion. Increasing or decreasing metabolism or excretion can lead to a respective decrease or increase of xenobiotic half-life, thus altering disposition. Expression of phase I [e.g., cytochromes P450 (P450s 1 )] and phase II enzymes [e.g., glucuronosyltransferases and sulfotransferases (STs)] is critical to metabolic processes, whereas transport proteins are vital for excretion. Interestingly, some enzymes and transporters are expressed in a gender-specific manner.

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“…The Na ϩ -dependent hepatic uptake of taurocholate is higher in male than in female rats (30). The uptake of tetraethylammonium, but not para-aminohippuric acid, by isolated kidney slices is higher in male than in female rats (5). Urinary excretion of xenobiotics, especially organic anions such as torasemide and zenarestat, shows gender differences: these compounds are excreted into the urine in much higher concentrations by female than by male rats, whereas this gender difference is minimal in humans (18,33,35).…”

mentioning

confidence: 87%

Gender difference in the Oatp1-mediated tubular reabsorption of estradiol 17β-d-glucuronide in rats

Gotoh

Kato

Stieger

et al. 2002

American Journal of Physiology-Endocrinology and Metabolism

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difference in the urinary excretion of estradiol-17␤-glucuronide (E2-17␤G) was examined in rats. The urinary clearance of E 2-17␤G was Ͼ250 times lower in male than in female rats. No such major gender difference was observed in its biliary excretion or metabolism in kidney homogenate. Both plasma protein binding and inulin clearance were comparable in male and female rats, suggesting that this gender difference cannot be explained by glomerular filtration. The urinary clearance with respect to the plasma unbound E 2-17␤G in male rats was Ͻ1% of the glomerular filtration rate, indicating its potential reabsorption by the kidney, and this increased to a level comparable with that found in female rats when dibromosulfophthalein was coinfused. A marked increase in E2-17␤G urinary excretion was also observed in male rats that had undergone orchidectomy. Testosterone injections given to female rats reduced the urinary excretion to a level comparable with that of control male rats. The concomitant change in the expression of the gene product for organic anion-transporting polypeptide Oatp1, of which E2-17␤G is a typical substrate, was found in the kidney membrane fractions after these treatments. These results suggest that urinary E2-17␤G excretion is subject to hormonal regulation and that the large gender difference can be explained by regulation in Oatp1-mediated reabsorption. gender difference; urinary excretion; reabsorption; organic anion-transporting polypeptide 1; multispecific resistanceassociated protein 2 THE DISPOSITION PROFILES of a number of xenobiotics exhibit gender differences, especially as far as animals are concerned (9, 12-14, 21, 23, 31-33, 35, 36). Hormonal regulation of the expression of certain types of metabolizing enzymes has been demonstrated. For example, CYP2C11 and 2C12 isoforms in liver microsomes are controlled by the plasma concentration profile of growth hormone, which is negatively and positively regulated by somatostatin and growth hormone-releasing factor, respectively, after stimulation by testosterone and estrogen (25). In another case, the metabolism of indinavir, probably due to CYP3A isoforms, exhibits a larger gender difference in rats, whereas the difference is relatively small in both monkeys and humans (20).Gender differences have also been reported in hepatic and renal uptake and/or excretion. The Na ϩ -dependent hepatic uptake of taurocholate is higher in male than in female rats (30). The uptake of tetraethylammonium, but not para-aminohippuric acid, by isolated kidney slices is higher in male than in female rats (5). Urinary excretion of xenobiotics, especially organic anions such as torasemide and zenarestat, shows gender differences: these compounds are excreted into the urine in much higher concentrations by female than by male rats, whereas this gender difference is minimal in humans (18,33,35).Although the molecular mechanism for such gender differences in xenobiotic excretion is not yet fully characterized, several transporters have been shown to exhibit gender-...

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Postnatal development of sex differences in renal tubular transport of p-aminohippurate (PAH) in rats

Cited by 23 publications

References 13 publications

Sex Differences in the mRNA, Protein, and Functional Expression of Organic Anion Transporter (Oat) 1, Oat3, and Organic Cation Transporter (Oct) 2 in Rabbit Renal Proximal Tubules

Sex Differences in the mRNA, Protein, and Functional Expression of Organic Anion Transporter (Oat) 1, Oat3, and Organic Cation Transporter (Oct) 2 in Rabbit Renal Proximal Tubules

Endocrine Regulation of Rat Organic Anion Transporters

Gender difference in the Oatp1-mediated tubular reabsorption of estradiol 17β-d-glucuronide in rats

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