MECHANISMS UNDERLYING REGIOSELECTIVE ACUTE TUBULAR NECROSIS OF RENAL PROXIMAL TUBULAR SEGMENTS

The convoluted (CPT) and straight (SPT) portions of the renal proximal tubule are susceptible to injury by a wide variety of chemical agents. These agents often affect the CPT or SPT selectively by proposed mechanisms usually attributed to tubular concentration, blood flow delivery patterns and tubuloglomerular feedback responses within the intact kidney. The innate cellular responses to chemical exposures remain virtually unexplored. Hence, the basic goal of this research was to develop an in vitro system that was conducive to examining the innate cellular differences in susceptibility between the CPT and SPT following in vitro exposure to mercuric chloride (HgCl₂), potassium dichromate (K₂Cr₂O₇)$ or hypoxic conditions. A renal cortical slicing technique was developed for these studies to position the CPT and SPT within discrete regions of slices made perpendicular to the cortical-papillary axis. An incubation vessel that could maintain the morophological and biochemical viability of slices for at least 12 hr was also developed. The selective necrosis of CPT induced by K₂Cr₂O₇ or hypoxic exposure, and SPT induced by HgCl₂, observed in vivo was reproduced in renal cortical slices exposed in vitro. Innate cellular uptake mechanisms were then investigated since the tissue distribution of each metal was found to be most concentrated within their respective injured cell type. The transport of PAH, TEA, phosphate, sulfate, glutathione and cysteine were examined as potential mechanisms for selective accumulation of these metals. K₂Cr₂O₇ caused a dose-dependent reduction in the uptake rate of sulfate by cortical slices, while phosphate, PAH, and TEA uptake were unaffected. Although HgCl₂ has a high affinity for sulfhydryl groups its uptake as a complex to glutathione or cysteine was not enhanced. HgCl₂ also had no affect on the uptake rate of PAH or TEA even though both HgCl₂ and K₂Cr₂O₇ were able to reduce the steady state accumulation of these organic substrates