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 (mu-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 mu-36/NL4-3/CIDHP but increased in NL4-3/CIDHP. Acute knockdown of Foxo3a by small interfering RNA induced a 50% increase in mu-36/NL4-3/CIDHP apoptosis, indicating that Foxo3a-dependent responses promote the survival phenotype in mu-36 cells. We conclude that inhibition of p66ShcA redox activity prevents generation of HIV-1 stress signals and activation of the CIDHP apoptosis program.Glomerular visceral epithelial cells or podocytes are highly specialized cells that play a pivotal role in the pathogenesis of focal segmental glomerular sclerosis (FSGS) and the collapsing variant of this entity, frequently encountered in HIVAN. The podocyte, strategically positioned along the glomerular basement membrane, is a critical component of the glomerular filtration barrier, functioning in tandem with its associated slit diaphragm to limit passage of albumin and plasma proteins to the urinary space (1, 2). Compelling evidence (3-7) supports a key role for HIV-1 gene products in the podocyte injury that leads to a breach in the integrity of the glomerular filtration barrier and the massive proteinuria that characterizes HIVAN. The absence of podocyte regeneration after cell injury or apoptosis is a major limitation to the development of innovative therapeutic strategies to arrest or prevent HIVAN and other glomerular diseases. Accordingly, interventions that increase the resistance of this terminally differentiated cell population to death signals offer a novel approach to preserve the integrity and permselectivity of the glomerular filtration barrier.Several lines of evidence support a dominant role for the p66ShcA protein in the intracellular pathways that convert oxidative stress to apoptosis (8, 9). The three overlapping Shc proteins, p66ShcA, p52ShcA, and p46ShcA, share a C-terminal Src homology 2 domain, central collagen homology region, and N-terminal phosphotyrosine binding domain. p46ShcA and p52ShcA are the product of alternative translation initiation sites within the same transcript, wherea...

HighlightsQuercetin-3-glucoside can increase LDLR expression by hepatocytes.Quercetin-3-glucoside can reduce PCSK9 secretion by hepatocytes.Quercetin-3-glucoside can down regulate sortilin expression.Quercetin-3-glucoside can increase LDL uptake by hepatocytes.Quercetin-3-glucoside is a potential anti-cholesterolemic agent.

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