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Hypoxic rise in cytosolic calcium and renal proximal tubule injury mediated by a nickel-sensitive pathway.

Abstract
In the kidney, cell injury resulting from ischemia and hypoxia is thought to be due, in part, to increased cytosolic Ca(2+) levels, [Ca(2+)]i, leading to activation of lytic enzymes, cell dysfunction, and necrosis. We report evidence of a progressive and exponential increase in [Ca(2+)]i (from 245 +/- 10 to 975 +/- 100 nM at 45 mins), cell permeabilization and propidium iodide (PI) staining of the nucleus, and partial loss of cell transport functions such as Na(+)-gradient-dependent uptakes of (14)C-alpha-methylglucopyranoside and inorganic phosphate ((32)Pi) in proximal convoluted tubules of adult rabbits subjected to hypoxia. The rise in [Ca(2+)]i depended on the presence of extracellular [Ca(2+)] and could be blocked by 50 microM Ni(2+)but not by verapamil (100 microM). Presence of 50 microM Ni(2+) also reduced the hypoxia-induced morphological and functional injuries. We also used HEK 293 cells, a kidney cell line, incubated in media without glucose and exposed for 3.5 hrs to 1% O(2)-5% CO(2) and then returned to glucose-containing media for another 3.5 hrs in an air-5% CO(2) atmosphere and finally exposed for 1 min to media containing 1 microM PI. NiCl(2) (50 microM) or pentobarbital (300 microM) more than phenobarbital (1.5 mM), when present in the incubation medium during both the hypoxic and the reoxygenation periods, induced significant (P < 0.001) reductions in the number of cell nuclei stained with PI, similar to their relative potency as inhibitors of T channels. Our findings indicate that hypoxia-induced alterations in calcium level and subsequent cell injury in the proximal convoluted tubule and in HEK cells involve a nickel-sensitive and dihydropyridine insensitive pathway or channel.
AuthorsM Barac-Nieto, A Constantinescu, M H Pina-Benabou, R Rozental
JournalExperimental biology and medicine (Maywood, N.J.) (Exp Biol Med (Maywood)) Vol. 229 Issue 11 Pg. 1162-8 (Dec 2004) ISSN: 1535-3702 [Print] England
PMID15564443 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Calcium Channel Blockers
  • GABA Modulators
  • Nickel
  • Verapamil
  • Pentobarbital
  • Calcium
  • Phenobarbital
Topics
  • Animals
  • Calcium (metabolism)
  • Calcium Channel Blockers (pharmacology)
  • Cytoplasm (chemistry, drug effects, metabolism)
  • Female
  • GABA Modulators (pharmacology)
  • Humans
  • Hypoxia (physiopathology)
  • Kidney Tubules, Proximal (metabolism, pathology, physiopathology)
  • Nickel (metabolism)
  • Organ Culture Techniques
  • Pentobarbital (pharmacology)
  • Phenobarbital (pharmacology)
  • Rabbits
  • Tumor Cells, Cultured
  • Verapamil (pharmacology)

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