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The Death Ligand TRAIL in Diabetic Nephropathy

Corina Lorz^*, Alberto Benito-Martín^*, Anissa Boucherot, Alvaro C. Ucero^*, Maria Pia Rastaldi, Anna Henger, Silvia Armelloni, Beatriz Santamaría^*, Celine C. Berthier, Matthias Kretzler, Jesus Egido^* and Alberto Ortiz^*

^* Renal and Vascular Research Laboratory, Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Madrid, Spain; Division of Nephrology, University of Michigan, Ann Arbor, Michigan; and Renal Immunopathology Laboratory, Fondazione D'Amico per la Ricerca sulle Malattie Renali, c/o San Carlo Borromeo Hospital, Milan, Italy

Correspondence: Dr. Alberto Ortiz, Dialysis Unit, Fundación Jiménez Díaz, Avd. Reyes Católicos 2, 28040 Madrid, Spain. Phone: 34-91-5504940; Fax: 34-91-5442636; E-mail: aortiz{at}fjd.es; or Dr. Matthias Kretzler, Division of Nephrology, University of Michigan, 1570 MSRB II, 1150 W. Medical Center Drive, Ann Arbor, MI 48109-0676. Phone: 734-764-3157; Fax: 734-763-0982; E-mail: kretzler{at}umich.edu

Received for publication May 18, 2007. Accepted for publication November 29, 2007.

Apoptotic cell death contributes to diabetic nephropathy (DN), but its role is not well understood. The tubulointerstitium from DN biopsy specimens was microdissected, and expression profiles of genes related to apoptosis were analyzed. A total of 112 (25%) of 455 cell death–related genes were found to be significantly differentially regulated. Among those that showed the greatest changes in regulation were two death receptors, OPG (the gene encoding osteoprotegerin) and Fas, and the death ligand TRAIL. Glomerular and proximal tubular TRAIL expression, assessed by immunohistochemistry, was higher in DN kidneys than controls and was associated with clinical and histologic severity of disease. In vitro, proinflammatory cytokines but not glucose alone regulated TRAIL expression in the human proximal tubular cell line HK-2. TRAIL induced tubular cell apoptosis in a dosage-dependant manner, an effect that was more marked in the presence of high levels of glucose and proinflammatory cytokines. TRAIL also activated NF-B, and inhibition of NF-B sensitized cells to TRAIL-induced apoptosis. It is proposed that TRAIL-induced cell death could play an important role in the progression of human DN.

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