Deletion of podocyte STAT3 mitigates the entire spectrum of HIV-1-associated nephropathy.

Human immunodeficiency virus-1 (HIV-1)-associated nephropathy (HIVAN) is a leading cause of end stage renal disease among HIV-1 seropositive patients with advanced HIV disease. Renal parenchymal features of HIVAN include focal segmental glomerulosclerosis, podocyte dedifferentiation and proliferation, tubular cell apoptosis, and tubular microcystic dilation [1]. With widespread use of combination anti-retroviral therapy (cART), the impact of HIVAN has been dramatically reduced [2, 3]. In spite of cART, however, some HIV-1 seropositive patients still progress to end stage renal failure. Furthermore, HIVAN remains a major health issue in Africa [4]. HIV-1 expression in the kidney epithelial cells is thought to be responsible for HIVAN pathogenesis [5]. When non-structural components of the HIV-1 genome [6] or the gene encoding for the HIV-1 accessory protein nef [7] were over-expressed in podocytes of transgenic mice, podocytes de-differentiated and acquired a proliferative phenotype. nef activates signal transducer and activator of transcription (STAT) 3 signaling and drives dedifferentiation and proliferation of cultured podocyte [8]. Consistent with this, STAT3 signaling is activated in podocytes of patients with HIVAN and the Tg26 murine model of HIVAN [8]. We demonstrated previously that Tg26 mice with global reduction of STAT3 activity were protected from the development of HIVAN, which suggests that STAT3 is required for podocyte proliferation [9]. However, since STAT3 expression is ubiquitous and reduction of STAT3 activity in our previous murine model was not cell specific, we could not distinguish the relative importance of STAT3 in different cell types (i.e. kidney vs. infiltrating inflammatory cells) for HIVAN pathogenesis. Here, we specifically examined the role of podocyte STAT3 on the development of HIVAN.