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The role of cysteine proteases in hypoxia-induced rat renal proximal tubular injury.

Abstract
The role of the lysosomal proteases cathepsins B and L and the calcium-dependent cytosolic protease calpain in hypoxia-induced renal proximal tubular injury was investigated. As compared to normoxic tubules, cathepsin B and L activity, evaluated by the specific fluorescent substrate benzyloxycarbonyl-L-phenylalanyl-L-arginine-7-amido-4-methylcoumarin, was not increased in hypoxic tubules or the medium used for incubation of hypoxic tubules in spite of high lactate dehydrogenase (LDH) release into the medium during hypoxia. These data in rat proximal tubules suggest that cathepsins are not released from lysosomes and do not gain access to the medium during hypoxia. An assay for calpain activity in isolated proximal tubules using the fluorescent substrate N-succinyl-Leu-Tyr-7-amido-4-methylcoumarin was developed. The calcium ionophore ionomycin induced a dose-dependent increase in calpain activity. This increase in calpain activity occurred prior to cell membrane damage as assessed by LDH release. Tubular calpain activity increased significantly by 7.5 min of hypoxia, before there was significant LDH release, and further increased during 20 min of hypoxia. The cysteine protease inhibitor N-benzyloxycarbonyl-Val-Phe methyl ester (CBZ) markedly decreased LDH release after 20 min of hypoxia and completely prevented the increase in calpain activity during hypoxia. The increase in calpain activity during hypoxia and the inhibitor studies with CBZ therefore supported a role for calpain as a mediator of hypoxia-induced proximal tubular injury.
AuthorsC L Edelstein, E D Wieder, M M Yaqoob, P E Gengaro, T J Burke, R A Nemenoff, R W Schrier
JournalProceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 92 Issue 17 Pg. 7662-6 (Aug 15 1995) ISSN: 0027-8424 [Print] United States
PMID7644473 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Dipeptides
  • Serine Proteinase Inhibitors
  • N-benzyloxycarbonyl-valyl-phenylalanine methyl ester
  • Ionomycin
  • Cathepsins
  • Endopeptidases
  • Calpain
  • Cysteine Endopeptidases
  • Cathepsin B
  • Cathepsin L
  • Ctsl protein, rat
Topics
  • Animals
  • Calpain (metabolism)
  • Cathepsin B (metabolism)
  • Cathepsin L
  • Cathepsins (metabolism)
  • Cysteine Endopeptidases (metabolism)
  • Dipeptides (pharmacology)
  • Endopeptidases
  • Hypoxia
  • In Vitro Techniques
  • Ionomycin (pharmacology)
  • Kidney Cortex (drug effects, pathology, physiopathology)
  • Kidney Tubules, Proximal (drug effects, pathology, physiopathology)
  • Kinetics
  • Male
  • Rats
  • Rats, Sprague-Dawley
  • Reference Values
  • Serine Proteinase Inhibitors (pharmacology)

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