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Basolateral membrane transporters of organic anions and cations in experimental cadmium nephrotoxicity in rat

Cadmium (Cd)-intoxicated experimental animals exhibit impaired renal secretion of organic anions (OA) and cations (OC), indicating relevant transporters (Oat1/Slc22a6, Oat3/Slc22a8, Oct1/Slc22a1, Oct2/Slc22a2) in the proximal tubule (PT) basolateral membrane (BLM) as possible targets of Cd. To correlate previous transport data with the expression of relevant transporters in experimental Cd- nephrotoxicity, we performed the immunochemical and RT-PCR studies of renal Oats and Octs in rats treated with CdCl2 for two weeks (subchronic model) or Cd-metallothionein (CdMT) for 6-12 hours (acute model). In both models, PT exhibited loss of basolateral invaginatios. In subchronic model, the expression of Oat1, Oat3, Oct1, and Oct2 proteins and their mRNAs was strongly downregulated. In acute model, a progressive loss of transporters from the BLM and their internalization and accumulation in intracellular organelles was observed. However, as estimated at 6 hours following CdMT- treatment, the total abundance of Oat and Oct proteins in the tissue remained unchanged, whereas the expression of their mRNAs was heterogeneously diminished (Oats >Octs). In some PT cells, finding of a limited Oat1 immunoreactivity in the brush-border membrane indicated loss of cell polarity. As tested in rats treated with colchicine, redistribution of Oats and Octs in intracellular organelles in acute Cd-nephrotoxicity was independent on microtubules. Therefore, the diminished renal secretion of OA and OC in Cd-nephrotoxicity may result from: a) loss of BLM invaginations, b) loss of BLM transporters due to inhibition of intracellular vesicle trafficking, c) diminished mRNA-dependent synthesis of the transporter proteins, and d) loss of the PT cell polarity.

heavy metal toxicity ; immunochemistry ; organic anion transporters ; organic cation transporters ; kidney ; RT-PCR

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