Persistent Nf-kappab Activation in Renal Epithelial Cells in a Mouse Model of Hiv-associated Nephropathy.
From: Case Western Reserve University, MetroHealth Medical Center Campus, Rammelkamp Center R435, 2500 MetroHealth Drive, Cleveland, OH 44109, USA.
American journal of physiology. Renal physiology
- Publish Date: Mar 2006
- ISSN: 0363-6127
- Volume: 290
- Issue: 3
- Pages: F657-65
- Medium: Print
- Language: English
- Citation (JAMA): Martinka Scott, Bruggeman Leslie A, et al. Persistent Nf-kappab Activation in Renal Epithelial Cells in a Mouse Model of Hiv-associated Nephropathy.. Am. J. Physiol. Renal Physiol. Mar 2006;290:F657-65
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.
Mesh Headings (Keywords): AIDS-Associated Nephropathy, Animals, Dimerization, Disease Models, Animal, I-kappa B Proteins, Kidney, Mice, NF-kappa B, Phosphorylation, Reference Values, Tubulin, Urothelium
Check for Full Text / PubMed Unique Identifier (PMID): 16204413
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