PMID- 20404718
OWN - NLM
STAT- MEDLINE
DCOM- 20110331
LR  - 20211020
IS  - 1473-5571 (Electronic)
IS  - 0269-9370 (Print)
IS  - 0269-9370 (Linking)
VI  - 24
IP  - 8
DP  - 2010 May 15
TI  - HIV-1 viral protein r induces ERK and caspase-8-dependent apoptosis in renal 
      tubular epithelial cells.
PG  - 1107-19
LID - 10.1097/QAD.0b013e328337b0ab [doi]
AB  - 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.
FAU - Snyder, Alexandra
AU  - Snyder A
AD  - Department of Nephrology, Mount Sinai School of Medicine, New York, New York 
      10029, USA.
FAU - Alsauskas, Zygimantas C
AU  - Alsauskas ZC
FAU - Leventhal, Jeremy S
AU  - Leventhal JS
FAU - Rosenstiel, Paul E
AU  - Rosenstiel PE
FAU - Gong, Pengfei
AU  - Gong P
FAU - Chan, Justin J K
AU  - Chan JJ
FAU - Barley, Kevin
AU  - Barley K
FAU - He, John C
AU  - He JC
FAU - Klotman, Mary E
AU  - Klotman ME
FAU - Ross, Michael J
AU  - Ross MJ
FAU - Klotman, Paul E
AU  - Klotman PE
LA  - eng
GR  - R01DK078510/DK/NIDDK NIH HHS/United States
GR  - P01DK056492/DK/NIDDK NIH HHS/United States
GR  - HHMI/Howard Hughes Medical Institute/United States
GR  - R01 DK078510/DK/NIDDK NIH HHS/United States
GR  - P01 DK056492-09/DK/NIDDK NIH HHS/United States
GR  - R01 DK078510-03/DK/NIDDK NIH HHS/United States
GR  - P01 DK056492/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - AIDS
JT  - AIDS (London, England)
JID - 8710219
RN  - 0 (Gene Products, vpr)
RN  - 0 (RNA, Viral)
RN  - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
RN  - EC 3.4.22.- (Caspase 8)
SB  - IM
MH  - AIDS-Associated Nephropathy/genetics/*metabolism/virology
MH  - Apoptosis/genetics/*physiology
MH  - Caspase 8/genetics/*metabolism
MH  - Cell Proliferation
MH  - Extracellular Signal-Regulated MAP Kinases/*metabolism
MH  - Gene Expression Regulation, Viral
MH  - Gene Products, vpr/genetics/*metabolism
MH  - *HIV-1
MH  - Humans
MH  - Kidney Failure, Chronic/genetics/*metabolism/virology
MH  - Kidney Tubules/virology
MH  - RNA, Viral
MH  - Virus Replication
PMC - PMC2860650
MID - NIHMS190110
EDAT- 2010/04/21 06:00
MHDA- 2011/04/01 06:00
PMCR- 2011/05/15
CRDT- 2010/04/21 06:00
PHST- 2010/04/21 06:00 [entrez]
PHST- 2010/04/21 06:00 [pubmed]
PHST- 2011/04/01 06:00 [medline]
PHST- 2011/05/15 00:00 [pmc-release]
AID - 10.1097/QAD.0b013e328337b0ab [doi]
PST - ppublish
SO  - AIDS. 2010 May 15;24(8):1107-19. doi: 10.1097/QAD.0b013e328337b0ab.