Nef stimulates proliferation of glomerular podocytes through activation of Src-dependent Stat3 and MAPK1,2 pathways

Abstract

In collapsing focal segmental glomerulosclerosis (FSGS) of HIV-associated nephropathy (HIVAN),

Pathology of Pulmonary Hypertension

“…The localization and adaptor functions recruit signaling proteins to discrete regions in the membrane and affect T cell signaling pathways [97]. Proteins associated with a survival and pro-angiogenic phenotype in severe PH such as PI-3 kinase, MAP kinases, and a p21 kinase-2 are all recruited to the rafts by Nef [98][99][100][101]. In human monocyte-derived macrophages (MDMs), Nef activates the STAT1 pathway and the secretion of MIP-1, IL-1-α, IL-6, and TNF-α [102].…”

HIV-1 Upregulates VEGF in Podocytes

“…We found that only the nef gene was responsible for HIV-induced HIF-2␣ and VEGF expression in podocytes (Supplemental Figure 2). Because we have shown previously that Nef activates the Src/Stat3 pathway in podocytes 13 and the Src/Stat3 pathway has been shown to mediate HIF-2␣ expression in other cell lines, 14 we investigated whether Src/Stat3 mediates Nef-induced HIF-2␣ expression in podocytes. We found that both pp2 (a Src kinase inhibitor) as well as a dominant negative mutant for Stat3 inhibited Nef-induced HIF-2␣ expression, suggesting that the Src/Stat3 pathway indeed mediates the Nef-induced increase in HIF-2␣ expression in podocytes (Supplemental Figure 2E).…”

Retinoic Acid Utilizes CREB and USF1 in a Transcriptional Feed-Forward Loop in Order To Stimulate MKP1 Expression in Human Immunodeficiency Virus-Infected Podocytes

“…Unlike most other glomerulopathies, HIVAN is characterized by proliferation and dedifferentiation of podocytes, which are glomerular visceral epithelial cells (3,4,17). Recently, we showed that the HIV-1 nef gene is the primary determinant of this unusual podocyte phenotype (17,36) and that Nef stimulates podocyte proliferation and dedifferentiation through the Src-dependent mitogenactivated protein kinase 1,2 (MAPK1,2) pathways (15). Increased MAPK1,2 phosphorylation is also observed in mouse and human kidney sections of HIVAN (15).…”