engleski

Sex and species differences in renal transporters of organic compounds

In the mammalian kidneys, transport of various organic compounds (organic anions and cations, glucose) and water is mediated by specific proteins localized in the luminal and/or contraluminal cell membrane domains along the nephron, largely in proximal tubules. These transporters contribute to reabsorption and/or secretion of endogenous and xenobiotic organic compounds, including various anionic and cationic drugs that are used in human and veterinary medicine. Recent studies have shown that some of these transporters (“drug transporters”) contribute to development of drug resistance, drug-drug interactions, and drug-induced nephrotoxicity, whereas their malfunction due to truncated forms of proteins or point mutations in their genes can cause genetic diseases. In rodents (rats, mice, rabbits), many renal transporters exhibit sex differences in their protein and/or mRNA expression, whereas in pigs and humans, some transporters are absent, some exhibit localization in the cell membrane domains different from that in rodents, but the sex-related expression of thus far tested transporters could not been confirmed. For some transporters common to rodent, pig and human kidneys, species differences were observed in selectivity for substrates, distribution along the nephron, expression of mRNA and/or protein, sensitivity to inhibitors, and regulation of the activity. In addition, recent findings in this field in rodents revealed the species-related discrepancies in the expression of some transporters at the level of protein and their mRNA, e.g., sex differences in the transporter protein can exist with or without equivalent differences in the expression of its mRNA. Moreover, these two parameters can be in an opposite relationship. We, therefore, conclude the following: a) the data on renal transporters in one sex and species can not simply be regarded as relevant for other sex and species, b) posttranscriptional regulation may represent crucial mechanism in controlling the sex- and species-related protein expression of the renal transporters, c) various physiological, pharmacological, and toxicological findings related to the transporter-mediated handling of organic substances and water in the rodent kidneys do not reflect the situation in the pig and human kidneys, and d) the kidneys in pigs, not in rodents, may represent much better model for studying the human-related expression and functions of various renal transporters.

drug transporters; organic anions; organic cations; glucose transporters; aquaporins; sex differences; species differences; mammalian kidney

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