HIV-1 viral protein r induces ERK and caspase-8-dependent apoptosis in renal tubular epithelial cells.

Published

Journal Article

HIV-associated nephropathy (HIVAN) is the most common cause of end-stage renal disease in persons with HIV/AIDS and is characterized by focal glomerulosclerosis and dysregulated renal tubular epithelial cell (RTEC) proliferation and apoptosis. HIV-1 viral protein r (Vpr) has been implicated in HIV-induced RTEC apoptosis but the mechanisms of Vpr-induced RTEC apoptosis are unknown. The aim of this study was therefore to determine the mechanisms of Vpr-induced apoptosis in RTEC.Apoptosis and caspase activation were analyzed in human RTEC (HK2) after transduction with Vpr-expressing and control lentiviral vectors. Bax and BID were inhibited with lentiviral shRNA, and ERK activation was blocked with the MEK1,2 inhibitor, U0126.Vpr induced apoptosis as indicated by caspase 3/7 activation, PARP-1 cleavage and mitochondrial injury. Vpr activated both caspases-8 and 9. Inhibition of Bax reduced Vpr-induced apoptosis, as reported in other cell types. Additionally, Vpr-induced cleavage of BID to tBID and suppression of BID expression prevented Vpr-induced apoptosis. Since sustained ERK activation can activate caspase-8 in some cell types, we studied the role of ERK in Vpr-induced caspase-8 activation. Vpr induced sustained ERK activation in HK2 cells and incubation with U0126 reduced Vpr-induced caspase-8 activation, BID cleavage and apoptosis. We detected phosphorylated ERK in RTEC in HIVAN biopsy specimens by immunohistochemistry.These studies delineate a novel pathway of Vpr-induced apoptosis in RTEC, which is mediated by sustained ERK activation, resulting in caspase 8-mediated cleavage of BID to tBID, thereby facilitating Bax-mediated mitochondrial injury and apoptosis.

Full Text

Duke Authors

Cited Authors

  • Snyder, A; Alsauskas, ZC; Leventhal, JS; Rosenstiel, PE; Gong, P; Chan, JJK; Barley, K; He, JC; Klotman, ME; Ross, MJ; Klotman, PE

Published Date

  • May 2010

Published In

Volume / Issue

  • 24 / 8

Start / End Page

  • 1107 - 1119

PubMed ID

  • 20404718

Pubmed Central ID

  • 20404718

Electronic International Standard Serial Number (EISSN)

  • 1473-5571

International Standard Serial Number (ISSN)

  • 0269-9370

Digital Object Identifier (DOI)

  • 10.1097/QAD.0b013e328337b0ab

Language

  • eng