engleski

Loss of endocytosis in proximal tubules of cadmium-metallothionein-treated rats

The intracellular events that lead to tubular proteinuria, a very early symptom in cadmium (Cd)-induced nephropathy in mammals, are poorly understood. Our recent findings in rats acutely treated with Cd-metallothionein (CdMT), revealed a time-dependent removal of megalin from the proximal tubule (PT) cell brush-border membrane (BBM), and its redistribution into intracellular organelles (Sabolic et al., Kidney Int. 2002, in press). Megalin is a receptor involved in reabsorption of various filtered proteins, and its removal from the BBM may affect endocytosis. This possibility was studied by immunofluorescence and electron microscopy in kidney cryosections from CdMT-treated rats (0.4 mg/kg b.m., a single dose s.c.) that had been injected in vivo with a fluorescent marker, FITC-dextran (30 mg/rat, i.v., 15 min before sacrifice). The uptake of FITC-dextran was correlated with intracellular distribution of clathrin, a 160 kDa protein that plays a major role in clathrin-mediated endocytosis along the PT. In PT of CdMT-treated rats we observed: a) decrease of FITC-dextran endocytosis in the S1/S2 but not S3 PT segments, b) relocation of apical clathrin into an intracellular compartment and the basolateral membrane (BLM), c) accumulation of small vesicles in the subapical region, accompanied by shortening and focal loss of microvilli, and d) loss of BLM invaginations. These phenomena started 1 h following CdMT treatment and further developed for the next 12 h. The data indicate that internalization of the PT cell BBM (and BLM) and loss of cell polarity are very early events in Cd nephrotoxicity, that may result from disrupted intracellular vesicle trafficking. These processes may lead to a time-dependent loss of BBM transporters and shortening and loss of microvilli, as well as to the loss of BLM, with reabsorptive and secretory defects in the PT as the final result. Tubular proteinuria in Cd nephrotoxicity may be an early, but secondary symptom resulting partially from the loss of apical megalin and clathrin, and partially from the loss of reabsorptive surface in PT.

brush-border membrane; heavy metal nephrotoxicity; kidney; proteinuria

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