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-kappaB, and inhibition of NF-kappaB 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.