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

AIDS. 2010 May 15;24(8):1107-19. doi: 10.1097/QAD.0b013e328337b0ab.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • AIDS-Associated Nephropathy / genetics
  • AIDS-Associated Nephropathy / metabolism*
  • AIDS-Associated Nephropathy / virology
  • Apoptosis / genetics
  • Apoptosis / physiology*
  • Caspase 8 / genetics
  • Caspase 8 / metabolism*
  • Cell Proliferation
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • Gene Expression Regulation, Viral
  • Gene Products, vpr / genetics
  • Gene Products, vpr / metabolism*
  • HIV-1*
  • Humans
  • Kidney Failure, Chronic / genetics
  • Kidney Failure, Chronic / metabolism*
  • Kidney Failure, Chronic / virology
  • Kidney Tubules / virology
  • RNA, Viral
  • Virus Replication

Substances

  • Gene Products, vpr
  • RNA, Viral
  • Extracellular Signal-Regulated MAP Kinases
  • Caspase 8