022-0222148-2146 Mammalian Renal Transporters; Gender Differences and Effects of Toxic Metals


Principal Investigator: Ivan Sabolić

The kidney secretes various organic anions (OA) and cations (OC), including most of drugs. This secretion takes place predominantly in the proximal tubules, and is mediated by specific transporters (OAT, OCT), localized in the cell membrane. Recent studies have shown that these transporters also mediate the cellular uptake of nephrotoxic metals (Cd, Hg, cis-Pt) by molecular mimicry; the metal binds to OA or OC, and the complex is then transferred into the cell by OAT or OCT. So far several isoforms of OAT and OCT have been described in the mammalian nephron, but their detailed distribution in the cells, and their relative abundance among species are poorly known. Adult rodents (rat, mouse) express gender (sex) differences in the renal excretion of some organic substances due to different expressions of OAT and OCT. Examples of the sex-related excretion of organic ions exist also in pigs and humans, but the expression of their transporters along the nephron in these species has not been examined in detail. Since the levels of sex hormones depend on sex, age, and hormonal cycle (women), the expression of the transporters may affect the reabsorption, secretion and toxicity of drugs, metals, or other substances in the tubules. Furthermore, it is well known that the nephrotoxic metals cause damage to the renal tubules, resulting in the loss of organic and inorganic substances in urine, and that metal toxicity in female rodents is weaker than in males, but possible mechanisms of these effects via expression of OAT, OCT, and other transporters along the nephron are not known. Here we propose biochemical, immunochemical, and molecular biology studies in order to compare the presence and distribution of OAT, OCT, and other transporters of organic substances in the rat, mouse, pig, and human kidneys. Using experimental animals of different sex, age, and hormonal cycle, we will study the effects of sex hormones and nephrotoxic metals on the expression of these transporters along the nephron. We expect that the final data will: a) show the presence of gender and species differences in the expression of various transporters in the cells along the nephron, b) identify an optimal animal model for the studies relevant to humans, and c) contribute to a better understanding of sex-dependent problems in therapy, (re)absorption and secretion of various drugs, and nephrotoxicity of some drugs, metals and other substances in mammals.