Dysregulated apoptosis of renal tubular epithelial cells (RTEC) is an important component of the pathogenesis of several renal diseases, including HIV-associated nephropathy (HIVAN), the most common cause of chronic kidney failure in HIV-infected patients. In HIVAN, RTEC become infected by HIV-1 in a focal distribution, and HIV-1 infection has been shown to induce apoptosis in vitro. In microarray studies that used a novel renal tubular epithelial cell line from a patient with HIVAN, it was found that the ubiquitin-like protein FAT10 is one of the most upregulated genes in HIV-infected cells. Previously, FAT10 was shown to induce apoptosis in murine fibroblasts. The expression of FAT10 in HIVAN and the ability of FAT10 to induce apoptosis in human RTEC therefore were studied. This study revealed that FAT10 expression is induced after infection of RTEC by HIV-1 and that expression of FAT10 induces apoptosis in RTEC in vitro. Moreover, it was found that inhibition of endogenous FAT10 expression abrogated HIV-induced apoptosis of RTEC. Immunohistochemical studies demonstrated increased FAT10 expression in a murine model of HIVAN, in HIVAN biopsy samples, and in autosomal dominant polycystic kidney disease, another renal disease that is characterized by cystic tubular enlargement and epithelial apoptosis. These results suggest a novel role for FAT10 in epithelial apoptosis, which is an important component of the pathogenesis of many renal diseases.