HIV-1 viral protein r induces ERK and caspase-8-dependent apoptosis in renal tubular epithelial cells.
Journal Article (Journal Article)
OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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 15, 2010
Published In
Volume / Issue
- 24 / 8
Start / End Page
- 1107 - 1119
PubMed ID
- 20404718
Pubmed Central ID
- PMC2860650
Electronic International Standard Serial Number (EISSN)
- 1473-5571
Digital Object Identifier (DOI)
- 10.1097/QAD.0b013e328337b0ab
Language
- eng
Conference Location
- England