Abstract
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.
Original language | English (US) |
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Pages (from-to) | 1107-1119 |
Number of pages | 13 |
Journal | AIDS |
Volume | 24 |
Issue number | 8 |
DOIs | |
State | Published - May 2010 |
Externally published | Yes |
Keywords
- AIDS-associated nephropathy
- Apoptosis
- Caspases
- Extracellular signal-regulated MAP kinases
- Kidney
- Vpr
ASJC Scopus subject areas
- Immunology and Allergy
- Immunology
- Infectious Diseases