Calpain activation and secretion promote glomerular injury in experimental glomerulonephritis: evidence from calpastatin-transgenic mice.
Glomerular injury and albuminuria in acute glomerulonephritis are related to the severity of inflammatory process. Calpain, a calcium-activated cysteine protease, has been shown to participate in the development of the inflammatory process. Therefore, for determination of the role of calpain in the pathophysiology of acute glomerulonephritis, transgenic mice that constitutively express high levels of calpastatin, a calpain-specific inhibitor protein, were generated. Wild-type mice that were subjected to anti-glomerular basement membrane nephritis exhibited elevated levels of calpain activity in kidney cortex at the heterologous phase of the disease. This was associated with the appearance in urine of calpain activity, which originated potentially from inflammatory cells, abnormal transglomerular passage of plasma proteins, and tubular secretion. In comparison with nephritic wild-type mice, nephritic calpastatin-transgenic mice exhibited limited activation of calpain in kidney cortex and limited secretion of calpain activity in urine. This was associated with less severe glomerular injury (including capillary thrombi and neutrophil activity) and proteinuria. There was a reduction in NF-kappaB activation, suggesting that calpain may participate in inflammatory lesions through NF-kappaB activation. There also was a reduction in nephrin disappearance from the surface of podocytes, indicating that calpain activity would enhance proteinuria by affecting nephrin expression. Exposure of cultured podocytes to calpain decreased nephrin expression, and, conversely, exposure of these cells to calpastatin prevented TNF-alpha from decreasing nephrin expression, demonstrating a role for the secreted form of calpain. Thus, both activation and secretion of calpains participate in the development of immune glomerular injury.
Peltier
Julie
J
INSERM U702, 7Université Pierre et Marie Curie-Paris6, UMRS702, Paris, France.
Bellocq
Agnès
A
Perez
Joëlle
J
Doublier
Sophie
S
Dubois
Yi-Chun Xu
YC
Haymann
Jean-Philippe
JP
Camussi
Giovanni
G
Baud
Laurent
L
D000419:Albuminuria / Q000209:etiology; D000818:Animals; D019867:Anti-Glomerular Basement Membrane Disease / Q000139:chemically induced; D002135:Calcium-Binding Proteins / Q000235:genetics*; D002154:Calpain / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000652:urine; D015853:Cysteine Proteinase Inhibitors / Q000235:genetics*; D004195:Disease Models, Animal; D005260:Female; D005921:Glomerulonephritis / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism; D007668:Kidney / Q000378:metabolism* / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism
D002135:Calcium-Binding Proteins; D015853:Cysteine Proteinase Inhibitors; D016328:NF-kappa B; C033668:calpastatin; D002154:Calpain