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Calpain Activation and Secretion Promote Glomerular Injury in Experimental Glomerulonephritis: Evidence from Calpastatin-Transgenic Mice

Julie Peltier^*,, Agnès Bellocq^*,,, Joëlle Perez^*, Sophie Doublier, Yi-Chun Xu Dubois^*,,, Jean-Philippe Haymann^*,,, Giovanni Camussi and Laurent Baud^*,,

^* INSERM, U702, Université Pierre et Marie Curie-Paris6, UMRS702, AP-HP, Tenon Hospital, Department of Physiology, Paris, France; and Center of Experimental Research and Medical Sciences, Department of Internal Medicine, University of Turin, Turin, Italy

Address correspondence to: Dr. Laurent Baud, INSERM U702, Hôpital Tenon, 4 rue de la Chine, 75020 Paris, France. Phone: +33-1-5601-7951; Fax: +33-1-5601-7003; E-mail: laurent.baud{at}tnn.ap-hop-paris.fr

Received for publication May 31, 2006. Accepted for publication September 26, 2006.

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-B activation, suggesting that calpain may participate in inflammatory lesions through NF-B 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- 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.

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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673