PubMed · 5551186
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J E Relton. 1971. Malignant hyperpyrexia: clinical aspects.. https://pubmed.ncbi.nlm.nih.gov/5551186/
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The kidney-specific chromatin structure of the phosphoenolpyruvate carboxykinase (PEPCK) gene was examined and compared to that of the liver. Kidney nuclear extracts were found to lack a liver-enriched factor, pepA, that binds to HSS A, a distal enhancer of the PEPCK gene that may be involved in opening the chromatin domain of the PEPCK gene in the liver. To begin the characterization of the kidney-specific chromatin structure of the PEPCK gene, nuclease hypersensitive sites (HSS) were mapped by indirect end-labeling analysis in proximal tubules from control rats, proximal tubules from acidotic rats which express induced levels of PEPCK, and NRK52E cells, a rat kidney epithelial cell line which does not express the PEPCK gene. A subset of HSS, at -400/+1 over the proximal promoter and at +1900 within the coding region, correlate with kidney-specific PEPCK expression. Two other HSS, at -3.1 kb and +6.2 kb, are detected in kidney cells regardless of PEPCK expression. The HSS at -4800, -1240, and +4650, previously identified in PEPCK-expressing liver cells, were not observed in the kidney. As in the liver, the pattern of hypersensitivity in the kidney does not change by altering the rate of transcription.
Amiloride and its more potent analog, hexamethylene amiloride (HMA), inhibits Na+ :H+ exchange and decreases intracellular pH in a concentration-dependent way in two human hepatocarcinoma cell lines and in a rat hepatocarcinoma cell line that differs in its phenotypic characteristics, resembling the clinical situation encountered in human hepatocarcinomas. After 24 h of exposure, DNA synthesis and cell protein content of the cultures decreases according to the concentration of the drugs and in parallel to Na+ exchange inhibition and the drop in pHi promoted. RNA and protein syntheses are less sensitive to its action. The above effects induced by HMA are accompanied by an abrupt decrease in cell viability and lysosomal integrity at 24 h. These effects develop gradually with the exposure time as does the increase in free radical production. Decreased viability is totally or partially restored by N-acetylcysteine or deferoxamine, but the degree of intracellular acidification produced is not. These results tend to suggest that intracellular acidification can diminish cell growth and provoke cytotoxic cell death by diminishing reduced glutathione (GSH) levels and impairing lysosomal integrity, reflecting the sensitivity of hepatocarcinoma cells to Na+ exchange inhibition and intracellular acidosis.
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