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Cadmium, mercury and cisplatin downregulate the expression of rat renal organic anion transporters Oat1 and Oat3

The secretion of para-aminohippurate (PAH) by the rat kidney and accumulation in the renal cortical slices is inhibited with various toxic metals (TM). The role of the major renal PAH transporters, OAT1 and OAT3, in that process has not been clarified. The aim of this study was to establish the effect of environmental TM (cadmium, Cd and mercury, Hg) and the TM used in medicine (cisplatin, cisPt) on PAH transporters. We used two immunochemical methods to study the effects of TM treatment on the localization and abundance of OAT1 and OAT3 proteins along the rat nephron. In addition we studied mRNA expression of both transporters by RT-PCR. OAT1 and OAT3 were localized on the basolateral membrane (BLM) of the epithelial cells in the proximal tubule (PT) ; OAT1 was strongly expressed in the PT S2 and weak in the S3 segments, whereas OAT3 was present in PT S1 and S2 segments. The expression of both transporters in rats treated with TM was examined only in the cortical tubules. In the established experimental models with each TM, OAT1 was reduced most strongly in Cd treated animals, whereas treatment with Hg and cisPt resulted in its partial and non significant decrease, respectively. Decrease in protein expression was in correlation with mRNA expression. The expression of OAT3 in the cortex after TM treatment largely followed a similar pattern. An exception was noticed in animals treated with cisPt where protein expression was significantly decreased but mRNA expression was only slightly downregulated. The doses of TM that cause decrease in PAH transport, also caused damage of BLM in PT, being very severe in S1 PT after treatment with Cd, and in S3 segments after treatment with Hg or cisPt. TM treatment caused significant, decrease of the expression of OAT1 (except for cisPt), and OAT3. The strongest effect on PAH transporters in our animal models was that of Cd, followed by Hg, and cisPt. Our data indicate that inhibition of PAH transport after TM treatment partly depend on the decreased cortical expression of OAT1 and OAT3 proteins in damaged BLM of PT.

kidney; para-aminohippurate; organic anion transporters; toxic metals

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