No description available.

The proximal tubule of the renal cortical nephron is highly susceptible to intoxication by chemical agents. An in vitro system was developed to study directly the effects of nephrotoxic chemicals on this renal sub-organ fraction without the complication of extrarenal factors. Segments of proximal tubules were isolated by a mechanical method from the kidneys of young rabbits. Tubules obtained by this method retained biochemical, functional, and morphological features comparable to those existing in vivo. Preliminary acute susceptibility studies demonstrated that the isolated proximal tubule segments were sensitive to a variety of known nephrotoxic agents that target the proximal tubule. These agents include halogenated hydrocarbons, heavy metals, and a halogenated vinyl cysteine conjugate. Incubation conditions were optimized to maintain the viability of proximal tubule suspensions for up to four hours. Longer incubation times made it possible to establish a chronology of early tubule responses to chemical intoxication. Long term incubation of proximal tubule suspensions with two model nephrotoxins, cadmium chloride and S-(trans-1,2-dichlorovinyl)-L-cysteine, produced in vitro tubule response patterns similar to those reported in vivo for these agents. While not entirely representative of in vivo exposure conditions, suspensions of isolated proximal tubules are an easily obtained system that proved equally applicable as a screening technique for nephrotoxic compounds or as an in vitro system for delineating proximal tubule response to chemical insult.

No description available.

No description available.

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.

Thesis (Ph. D.)--University of Hong Kong, 2005. / Title proper from title frame. Also available in printed format.

No description available.

Thesis (Ph. D.)--University of Texas Health Science Center at Houston, School of Public Health, 2007. / Source: Dissertation Abstracts International, Volume: 68-12, Section: B, page: 7975. Adviser: Mary Ann Smith. Includes bibliographical references.

Haloalkenes were shown to react with cysteine, N-acetyl cysteine, or glutathione to form halogenated vinylthio (HVT) or saturated conjugates. When HVT were administered iv to rabbits, active transport in the renal tubules was inhibited 50% at doses as low as 20 mg/kg within 1 hr after dosing. There was sloughing of the renal brush border membrane with the injury progressing to a specific renal tubular necrosis of the S₃ segment. In vitro studies with renal tubules found that the HVT produced a dose-response related inhibition of acid/base transport, with complete inhibition of transport occurring at 1 mM. The cysteine conjugate synthesized from trichloroethylene, DCVC, inhibited tubular active transport 60 min after in vivo dosing (20-100 mg/kg), 45 min after exposure in the isolated perfused kidney (0.01-1 mM) and 15 min after incubation with isolated tubules (0.01-1 mM). All HVT conjugates had a similar potency with regard to transport inhibition in isolated tubules, with complete inhibition occurring at 1 mM within 15 min for cysteine conjugates compared to 45-60 min for the N-acetyl cysteine or glutathione conjugates. These latter conjugates are thought to be bioactivated to the cysteine conjugate prior to transport inhibition. Inhibition of tubular (gamma)-glutamyl transpeptidase by 1 mM AT-125 or 20 mM serine/borate prevented the inhibition of acid/base transport by the glutathione conjugate. In addition, the sequential formation of glutamate, glycine and the vinyl cysteine conjugate after tubule incubation with the glutathione conjugate provides further evidence for this bioactivation. The cysteine conjugates are thought to be further metabolized in tubules to a toxic intermediate by a brush border localized enzyme, C-S lyase. The inhibitor effect of this intermediate on acid/base transport is reversed in the presence of, or subsequent addition of, 6 mM exogenous glutathione. These studies provide further evidence for the nephrotoxicity of HVT, and formation of the nephrotoxic cysteine conjugates from glutathione and cysteine conjugates. The formation of saturated conjugates from CTFE was also demonstrated. These saturated and/or unsaturated conjugates may be responsible for haloalkene-induced nephrotoxicity.

Thesis (Ph. D.)--University of Hong Kong, 2009. / Includes bibliographical references (leaves 166-185). Also available in print.