Inhibition of p66ShcA longevity gene rescues podocytes from HIV-1-induced oxidative stress and apoptosis.

Journal Article (Journal Article)

Glomerular visceral epithelial cells (podocytes) play a critical role in the pathogenesis of human immunodeficiency virus (HIV)-associated nephropathy. A key question concerns the mechanism(s) by which the HIV-1 genome alters the phenotype of the highly specialized, terminally differentiated podocytes. Here, using an in vitro system of conditionally immortalized differentiated human podocytes (CIDHPs), we document a pivotal role for the p66ShcA protein in HIV-1-induced reactive oxygen species generation and CIDHP apoptosis. CIDHP transfected with truncated HIV-1 construct (NL4-3) exhibit increased reactive oxygen species metabolism, DNA strand breaks, and a 5-fold increase in apoptosis, whereas the opposite was true for NL4-3/CIDHP co-transfected with mu-36p66ShcA (micro-36) dominant negative expression vector or isoform-specific p66-small interfering RNA. Phosphorylation at Ser-36 of the wild type p66ShcA protein, required for p66ShcA redox function and inhibition of the potent stress response regulator Foxo3a, was unchanged in micro-36/NL4-3/CIDHP but increased in NL4-3/CIDHP. Acute knockdown of Foxo3a by small interfering RNA induced a 50% increase in micro-36/NL4-3/CIDHP apoptosis, indicating that Foxo3a-dependent responses promote the survival phenotype in micro-36 cells. We conclude that inhibition of p66ShcA redox activity prevents generation of HIV-1 stress signals and activation of the CIDHP apoptosis program.

Full Text

Duke Authors

Cited Authors

  • Husain, M; Meggs, LG; Vashistha, H; Simoes, S; Griffiths, KO; Kumar, D; Mikulak, J; Mathieson, PW; Saleem, MA; Del Valle, L; Pina-Oviedo, S; Wang, JY; Seshan, SV; Malhotra, A; Reiss, K; Singhal, PC

Published Date

  • June 12, 2009

Published In

Volume / Issue

  • 284 / 24

Start / End Page

  • 16648 - 16658

PubMed ID

  • 19383602

Pubmed Central ID

  • PMC2713565

International Standard Serial Number (ISSN)

  • 0021-9258

Digital Object Identifier (DOI)

  • 10.1074/jbc.M109.008482

Language

  • eng

Conference Location

  • United States