BASIC RESEARCH

The Death Ligand TRAIL in Diabetic Nephropathy

Lorz, Corina^*; Benito-Marti[Combining Acute Accent]n, Alberto^*; Boucherot, Anissa^†; Ucero, Alvaro C.^*; Rastaldi, Maria Pia^‡; Henger, Anna^†; Armelloni, Silvia^‡; Santamari[Combining Acute Accent]a, Beatriz^*; Berthier, Celine C.^†; Kretzler, Matthias^†; Egido, Jesus^*; Ortiz, Alberto^*

Author Information

^*Renal and Vascular Research Laboratory, Fundacio[Combining Acute Accent]n Jime[Combining Acute Accent]nez Di[Combining Acute Accent]az, Universidad Auto[Combining Acute Accent]noma 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, Fundacio[Combining Acute Accent]n Jime[Combining Acute Accent]nez Di[Combining Acute Accent]az, Avd. Reyes Cato[Combining Acute Accent]licos 2, 28040 Madrid, Spain. Phone: 34-91-5504940; Fax: 34-91-5442636; E-mail: [email protected]; 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: [email protected]

Accepted November 29, 2007

Received May 18, 2007

Journal of the American Society of Nephrology 19(5):p 904-914, May 2008. | DOI: 10.1681/ASN.2007050581

Abstract

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-κB, and inhibition of NF-κB 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.