title: Persistent NF-kappaB activation in renal epithelial cells in a mouse model of HIV-associated nephropathy.
abstract: Human immunodeficiency virus (HIV)-associated nephropathy (HIVAN) is caused, in part, by direct infection of kidney epithelial cells by HIV-1. In the spectrum of pathogenic host-virus interactions, abnormal activation or suppression of host transcription factors is common. NF-kappaB is a necessary host transcription factor for HIV-1 gene expression, and it has been shown that NF-kappaB activity is dysregulated in many naturally infected cell types. We show here that renal glomerular epithelial cells (podocytes) expressing the HIV-1 genome, similar to infected immune cells, also have a dysregulated and persistent activation of NF-kappaB. Although podocytes produce p50, p52, RelA, RelB, and c-Rel, electrophoretic mobility shift assays and immunocytochemistry showed a predominant nuclear accumulation of p50/RelA-containing NF-kappaB dimers in HIV-1-expressing podocytes compared with normal. In addition, the expression level of a transfected NF-kappaB reporter plasmid was significantly higher in HIVAN podocytes. The mechanism of NF-kappaB activation involved increased phosphorylation of IkappaBalpha, resulting in an enhanced turnover of the IkappaBalpha protein. There was no evidence for regulation by IkappaBbeta or the alternate pathway of NF-kappaB activation. Altered activation of this key host transcription factor likely plays a role in the well-described cellular phenotypic changes observed in HIVAN, such as proliferation. Studies with inhibitors of proliferation and NF-kappaB suggest that NF-kappaB activation may contribute to the proliferative mechanism in HIVAN. In addition, because NF-kappaB regulates many aspects of inflammation, this dysregulation may also contribute to disease severity and progression through regulation of proinflammatory processes in the kidney microenvironment.
authors.affiliation: Case Western Reserve University, MetroHealth Medical Center Campus, Rammelkamp Center R435, 2500 MetroHealth Drive, Cleveland, OH 44109, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Martinka
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Bruggeman
mesh_terms: D016263:AIDS-Associated Nephropathy / Q000378:metabolism*; D000818:Animals; D019281:Dimerization; D004195:Disease Models, Animal; D020672:I-kappa B Proteins / Q000378:metabolism; D007668:Kidney / Q000378:metabolism*; D051379:Mice; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation; D012016:Reference Values; D014404:Tubulin / Q000378:metabolism; D019459:Urothelium / Q000378:metabolism*
chemical_list: D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D014404:Tubulin; D000072000:NF-KappaB Inhibitor alpha