Cytoprotection of kidney epithelial cells by compounds that target amino acid gated chloride channels

Manjeri A. Venkatachalam, Joel M. Weinberg, Yogendra Patel, Pothana Saikumar, Zheng Dong

Research output: Contribution to journalArticle

40 Citations (Scopus)

Abstract

Glycine, strychnine and certain chloride channel blockers were reported to protect cells against lethal cell injury. These effects have been attributed to interactions with membrane proteins related to CNS glycine gated chloride channel receptors. We have investigated the pharmacology of these actions. Madin-Darby canine kidney (MDCK) epithelial cells were depleted of adenosine triphosphate (ATP) by incubation in glucose free medium containing a mitochondrial uncoupler. Medium Ca2+ was adjusted to 100 nM in the presence of an ionophore such that intracellular Ca2+ did not increase, and Ca2+-related injury mechanisms were inhibited. This permitted more sensitive quantitation of protection against cell injury attributable to glycine or other agents whose actions might be related to those of the amino acid. Two classes of compounds showed cytoprotective activity in this system: (1) ligands at chloride channel receptors, such as glycine, strychnine and avermectin B1a; (2) chloride channel blockers, including cyanotriphenyl-boron and niflumic acid, both of which are known to bind to channel domains of CNS glycine receptors. Morphological and functional studies showed that the compounds preserved plasma membrane integrity, but permitted cell swelling. Substitution of medium chloride by gluconate, or chloride salts by sucrose, did not substantially modify lethal damage or its prevention by glycine or other drugs. The compounds did not modify ATP declines. At least for some compounds, cytoprotection appeared to be specific to structural features on the molecules. These observations are consistent with the hypothesis that a plasma membrane protein related to glycine-gated chloride channel receptors plays a significant role in cell injury, but indicate that the mechanisms of injury and protection by compounds active in this system are not related to chloride fluxes.

Original languageEnglish (US)
Pages (from-to)449-460
Number of pages12
JournalKidney International
Volume49
Issue number2
DOIs
StatePublished - Jan 1 1996
Externally publishedYes

Fingerprint

Chloride Channels
Cytoprotection
Glycine
Epithelial Cells
Kidney
Amino Acids
Wounds and Injuries
Chlorides
Strychnine
Membrane Proteins
Adenosine Triphosphate
Niflumic Acid
Cell Membrane
Glycine Receptors
Madin Darby Canine Kidney Cells
Boron
Ionophores
Sucrose
Blood Proteins
Salts

ASJC Scopus subject areas

  • Nephrology

Cite this

Cytoprotection of kidney epithelial cells by compounds that target amino acid gated chloride channels. / Venkatachalam, Manjeri A.; Weinberg, Joel M.; Patel, Yogendra; Saikumar, Pothana; Dong, Zheng.

In: Kidney International, Vol. 49, No. 2, 01.01.1996, p. 449-460.

Research output: Contribution to journalArticle

Venkatachalam, Manjeri A. ; Weinberg, Joel M. ; Patel, Yogendra ; Saikumar, Pothana ; Dong, Zheng. / Cytoprotection of kidney epithelial cells by compounds that target amino acid gated chloride channels. In: Kidney International. 1996 ; Vol. 49, No. 2. pp. 449-460.
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