engleski

Gender and species differences in renal organic anion and cation transporters

The kidneys maintain body fluid and electrolyte homeostasis using polarized localization of various transporters/carriers in the apical (luminal) and basolateral membrane domains of the cells along nephron. These transporters use ATP or transmembrane ion gradients to drive vectorial transport of their substrates in direction of secretion or reabsorption. The ATP-dependent carriers, termed ATP-binding casette transporters (Abc/ABC for animal/human transporters ; primary active transporters) and ATP-independent solute carriers (Slc/SLC for animal/human carriers ; secondary and terciary active transporters) are important for: a) handling of endogenous organic compounds that are produced during normal metabolism, such as organic anions (OA) and cations (OC), peptides, nucleosides, and their products, b) handling of exogenous (xenobiotic) organic compounds, such as food constituents (flavonoids, mycotoxins, pesticides, other alimentary organic substances), and drugs (various antibiotics and chemotherapeutics), c) drug-drug interactions, and d) development of nephrotoxicity and specific transporter-related diseases. Because of their major importance in drug transport and drug-mediated nephrotoxicity relevant to humans, a bulk of current research in the field of renal transporters has been dedicated to the roles of OA and OC transporters (Oats for animal/OATs for human, and Octs for animal/OCTs for human transporters, respectively). However, most of these data were obtained from the experiments in animals, largely rats and mice ; only a limited amount of data is from other animal species and humans. Recent observations in experimental animals and humans have indicated that renal secretory and reabsorptive functions under various physiological, pharmacological, and toxicological conditions may be different in males (M) and females (F), and that these differences may be related to sex hormone-regulated expression and action of specific transporters in one of the membrane domains of (mainly) proximal tubules (PT). Accordingly, a) M-dominant gender differences (GD) in renal excretion/clearance in rats and mice were observed for some OA, such as p-aminohippurate (PAH) and furosemide, due to androgen-stimulated expression of their carriers Oat1 and Oat3 in the PT basolateral membrane (BLM), b) renal accumulation and toxicity of mercury in rodents is M-dominant, because this toxic metal can enter the PT cells by molecular mimicry, e.g., bound to SH groups in some OA and thus transported via basolateral Oat1 and/or Oat3, c) M-dominant GD in renal handling of some OC in rats, such as tetraethylammonium (TEA), amantadine, and cisplatin, are determined by androgen-stimulated expression of Oct2 in the PT BLM, d) F-dominant renal clearance/excretion of various metabolic products and xenobiotics in rats (cyclacillin, carnitine, egualen sodium, perfluorooctanoic acid, estradiol-17 -glucuronide, taurocholate, dibromosulfophtalein, zenarestat) may be related to the lower expression of the respective transporters in the PT brush-border membrane (BBM) (Pept1, Octn2, Oatp1, Oat2), resulting in lower reabsorption of the filtered compounds in F. Where studied, the expression of several transporter (Oat1, Oat2, Oat3, Oat5, Oct2) were low and similar in M and F before the puberty ; GD occurred after the puberty. Contrary to the numerous cases of gender-dependent, carrier-mediated transport of specific organic compounds in rats and mice, a very few reports have been related to other species, including humans. In rabbits the expression of Oat1, Oat2, Oat3, and Oct2, in the PT significantly increased after the puberty, however without exhibiting sex differences in adult animals. Accordingly, rabbits exhibit no GD in urinary excretion of OA PAH and OC TEA. Some comparable data were also found in dogs. Furthermore, studies in humans showed that: a) the plasma level of acetylsalicylate, which is a substrate of several OATs (OAT1-4), was higher in F, b) the renal clearance of urate in F is higher than in M, possibly due to lower reabsorption of urate via weakly expressed URAT1 in the PT brush-border membrane, c) the renal clearances of the OA ciprofloxacin (a substrate of OATs), and of the OC amantadine (a substrate of OCT2), were found to be higher in M, but gender-related expression of the respective carriers in the human nephron has not been reported. Some other therapeutic drugs in humans (verapamil, metronidazole, vecuronium) also exhibit GD in their blood clearance, but a possible contribution of renal excretion/relevant transporters are not known. Humans and animals exhibit a similar set of renal transporters, but the presence, localization along the nephron, and intracellular localization of some carriers seem to be different from those in experimental animals. For example: a) Oat2 in rats and mice was localized to the PT BBM, whereas in humans, OAT2 was localized to the PT BLM, b) Oct1 was localized in the rat kidney largely to the PT BLM, whereas in the human kidney, OCT1 was not detected, c) Oct2 in the rat kidney was localized predominantly to the BLM of PT S3 segment, whereas OCT2 in the human kidney was localized to the BLM along the entire PT, and d) OAT4 in the human kidney was localized to the PT BBM, whereas a similar protein was absent from the rat nephron. These species differences in the expression and/or cellular localization of some transporters may influence the secretory and/or reabsorptive direction of renal transport of their substrates and thus may affect their urinary excretion. This further indicates that the findings regarding GD and effects of sex (and, possibly, other) hormones upon renal transporters in one species can not simply be regarded as relevant for other species.

gender differences; species differences; membrane transporters; organic anions; organic cations

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