HIV-1 Infection Initiates an Inflammatory Cascade in Human Renal Tubular Epithelial Cells

Abstract

HIV-associated nephropathy (HIVAN) is the most common cause of chronic renal failure in HIV-infected patients. Tubulointerstitial inflammation is a prominent component of the histopathology of HIVAN. The pathogenesis of HIVAN is a result of infection of renal epithelial cells, but the cellular response to this infection remains poorly defined. In these studies, we used oligonucleotide microarrays to identify differentially expressed genes in renal tubular epithelial cells from a patient with HIVAN at three time points after infection with vesicular stomatitis virus-pseudotyped gag/pol-deleted HIV-1. Very few genes were differentially expressed 12 and 24 hours after infection. Three days after infection, however, 47 genes were upregulated by at least 1.8-fold. The most prominent response of these cells to HIV-1 expression was production of proinflammatory mediators, including chemokines, cytokines, and adhesion molecules. Many of the upregulated genes are targets of interleukin 6 and nuclear factor kappa B regulation, suggesting a central role for these proteins in the response of tubular epithelial cells to HIV-1 infection. Analysis of kidneys from HIV-1 transgenic mice revealed upregulation of many of the proinflammatory genes identified in the microarray studies. These studies provide novel insights into the mechanisms by which HIV-1 infection of tubular epithelial cells leads to tubulointerstitial inflammation and progressive renal injury.

Renoprotective Effect of Combined Inhibition of Angiotensin-Converting Enzyme and Histone Deacetylase

“…These pathways are already known to be involved in HIVAN as well as in other kidney diseases. [25][26][27][28] We confirmed that SAHA affects more NFkB target genes in kidneys of Tg26 mice than does benazepril, whereas benazepril affects more Smad3 and p38 phosphorylation and oxidative stress (as measured by reduced glutathione and oxidized glutathione ratio) than SAHA ( Figure 5). It is known that activation of the angiotensin system induces Smad3 phosphorylation and oxidative stress [29][30][31] whereas HDAC interacts with the NFkB pathway.…”

The Ubiquitin-Like Protein FAT10 Mediates NF-κB Activation

“…Although the level of FAT10 mRNA upregulation was modest in biopsy samples, they are similar to the level of FAT10 upregulation in HIV-infected RTECs in our previous studies. 31 In conclusion, these studies elucidate a novel role for FAT10 in TNF-␣-induced NF-B activation and demonstrate that FAT10 is necessary for normal expression of LMP2 and degradation of IkB␣ in RTECs. Moreover, we have demonstrated that FAT10 expression is increased in the tubulointerstitium and expression levels are correlated with proteinuria and eGFR in the most common forms of chronic progressive renal dis- ease.…”

“…4,5,34 -36 In previous studies investigating the mechanisms by which HIV-1 induces renal disease, we infected human RTECs with HIV-1 to determine the genes that are differentially expressed in RTECs after HIV-1 infection. 31 The predominant response of these cells was increased production of cytokines, chemokines, and adhesion molecules. Hierarchical cluster analysis of the differentially expressed genes demonstrated that FAT10 was regulated similarly to several chemokines, including MCP-1 and CXCL2, which are regulated by NF-B.…”

“…26 FAT10 is constitutively expressed in mature dendritic cells and B cells 27,28 and is also inducible by the proinflammatory cytokines IFN-␥ and TNF-␣ in cells of various tissue origins 29,30 ; however, the role of FAT10 in the regulation of immune response has not been studied. Our observations that FAT10 is upregulated by HIV-1 infection of RTECs and that the pattern of FAT10 expression was similar to several other NF-B-regulated genes, 31 coupled with the knowledge that NF-B activation is controlled at multiple levels by the ubiquitin-proteasome system, led us to test the hypothesis that FAT10 participates in the regulation of NF-B activation.…”

In-Depth Review of Human Immunodeficiency Virus-Associated Nephropathy

“…Those histological characteristics of HIVAN are collapsing form of FSGS, microcystic tubular dilation and interstitial inflammation and fibrosis (Medapalli et al, 2011). (Vashistha et al, 2008;Kapasi et al, 2002;Ross et al, 2005;2006a;2006b). Furthermore, HIV infection of tubular epithelial cells also induces expression of multiple inflammatory mediators which may contribute to the prominent tubulointerstitial inflammation feature of HIVAN (Ross et al, 2006b).…”