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Persistent NF-B activation in renal epithelial cells in a mouse model of HIV-associated nephropathy

Department of Medicine and Rammelkamp Center for Education and Research, MetroHealth Medical Center, Case Western Reserve University School of Medicine, Cleveland, Ohio

Submitted 20 May 2005 ; accepted in final form 27 September 2005

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-B is a necessary host transcription factor for HIV-1 gene expression, and it has been shown that NF-B 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-B. 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-B dimers in HIV-1-expressing podocytes compared with normal. In addition, the expression level of a transfected NF-B reporter plasmid was significantly higher in HIVAN podocytes. The mechanism of NF-B activation involved increased phosphorylation of IB, resulting in an enhanced turnover of the IB protein. There was no evidence for regulation by IB or the alternate pathway of NF-B 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-B suggest that NF-B activation may contribute to the proliferative mechanism in HIVAN. In addition, because NF-B regulates many aspects of inflammation, this dysregulation may also contribute to disease severity and progression through regulation of proinflammatory processes in the kidney microenvironment.

podocyte; chronic renal disease; HIV-1; transcription

This article has been cited by other articles:

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