Extracellular calpains increase tubular epithelial cell mobility. Implications for kidney repair after ischemia.
Calpains are intracellular Ca2+-dependent cysteine proteases that are released in the extracellular milieu by tubular epithelial cells following renal ischemia. Here we show that externalized calpains increase epithelial cell mobility and thus are critical for tubule repair. In vitro, exposure of human tubular epithelial cells (HK-2 cells) to mu-calpain limited their adhesion to extracellular matrix and increased their mobility. Calpains acted primarily by promoting the cleavage of fibronectin, thus preventing fibronectin binding to the integrin alphavbeta3. Analyzing downstream integrin effects, we found that the cyclic AMP-dependent protein kinase A pathway was activated in response to alphavbeta3 disengagement and was essential for calpain-mediated increase in HK-2 cell mobility. In a murine model of ischemic acute renal failure, injection of a fragment of calpastatin, which specifically blocked calpain activity in extracellular milieu, markedly delayed tubule repair, increasing functional and histological lesions after 24 and 48 h of reperfusion. These findings suggest that externalized calpains are critical for tubule repair process in acute renal failure.
Frangié
Carlos
C
INSERM U702; Université Pierre et Marie Curie, 75020 Paris, France.
Zhang
Wenhui
W
Perez
Joëlle
J
Dubois
Yi-Chun Xu
YC
Haymann
Jean-Philippe
JP
Baud
Laurent
L
D000818:Animals; D002135:Calcium-Binding Proteins / Q000378:metabolism; D037281:Calnexin / Q000378:metabolism; D002154:Calpain / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002465:Cell Movement / Q000502:physiology*; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism*; D005353:Fibronectins / Q000378:metabolism; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism*; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology*
D002135:Calcium-Binding Proteins; D015853:Cysteine Proteinase Inhibitors; D005353:Fibronectins; D039302:Integrin alphaVbeta3; D020033:Protein Isoforms; D037281:Calnexin; C033668:calpastatin; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D002154:Calpain; C449002:mu-calpain