Cytoprotective properties of novel nonpeptide calpain inhibitors in renal cells

Xiuli Liu, Jay F. Harriman, Rick G. Schnellmann

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

Calpains are cytosolic, Ca2+, -activated, neutral cysteine proteases. Rabbit renal proximal tubule (RPT) cells express both μ- and m-calpain. Although multiple calpain inhibitors protect against RPT cell death, most calpain inhibitors lack specificity, membrane permeability, and/or potency. A group of novel catalytic site-directed calpain inhibitors, including chloroacetic acid N'-[6,7-dichloro-4-(4-methoxy-phenyl)-3-oxo-3,4-dihydroquinoxalin-2-yl] hydrazide (SJA7019) and chloroacetic acid N'-(6,7-dichloro-4-phenyl-3-oxo-3,4-dihydroquinoxalin-2-yl) hydrazide (SJA7029), were identified to be potent calpain inhibitors in vitro. The goals of this study were to determine the action of these two compounds on 1) RPT calpain activity using fluorescein isothiocyanate-casein zymography, 2) antimycin A-induced RPT extracellular 45Ca2+ influx and cell death, and 3) hypoxia/reoxygenation-induced RPT cellular dysfunction and death. The results showed that the SJA compounds inhibited RPT μ- and m-calpain with equal potency (approximate IC50, 30 μM) and efficacy, and blocked antimycin A-induced extracellular Ca2+ influx and cell death. In addition, SJA7029 blocked cell death and allowed the recovery of mitochondrial function and active Na+ transport in RPTs subjected to hypoxia/reoxygenation. In summary, the SJA compounds 1) were more potent inhibitors of calpains than catalytic site-directed peptide inhibitors in this model, 2) prevented extracellular Ca2+ influx during the late phase of cell death, and 3) are true cytoprotectants and allow recovery of RPT cellular functions after injury.

Original languageEnglish (US)
Pages (from-to)88-94
Number of pages7
JournalJournal of Pharmacology and Experimental Therapeutics
Volume302
Issue number1
DOIs
StatePublished - 2002
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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