Nuclear Factor kappa B (NF-kB) is a ubiquitous transcription factor that mediates immune and inflammatory processes. We have established that NF-kB is persistently activated in HIVAN, a collapsing glomerulopathy, which is characterized at the cellular level by defects in epithelial cell proliferation, apoptosis and differentiation. We hypothesize, in HIVAN, that a viral protein (likely Nef) associates with the NF-kB-activating signalsome and attenuates the normal, inactivating mechanism, resulting in persistence of NF-kB activation, and ultimately epithelial cell proliferation and immune cell recruitment and inflammation, key HIVAN phenotypes.
Specific aim 1 will identify the viral protein that causes persistent NF-kB activation, as well as the host signaling pathway it """"""""hijacks"""""""". Our preliminary data suggest interaction of the HIV protein Nef enhances IKK signalsome activity permitting persistent NF-kB activation, which can be suppressed by inhibition of TNF receptor signaling.
Specific aims 2 and 3 will test if NF-kB causes, in part, epithelial cell proliferation (aim 2) and immune cell recruitment and inflammation (aim 3). Abnormal epithelial proliferation is the major pathologic phenotype in HIVAN.
In specific aim 2, we propose increased epithelial proliferation results from NF-kB-dependent transcriptional regulation of Cyclin D1. Although we have shown in the first funding period that apoptosis is increased in HIVAN, we predict and will test if HIVAN-associated apoptosis is a compensatory response to increase epithelial cell proliferation.
In specific aim 3, we will investigate the role of NF-kB activation in immune cell recruitment by infected epithelial cells and in inflammation, a poorly defined aspect of HIVAN pathogenesis. Preliminary studies using in vitro migration assays as a model for immune cell recruitment indicate that the use of small molecule NF-kB inhibitors, CYC202 and BAY11-7082, are effective at suppressing chemoattractants produced by infected renal cells. Since NF-kB controls the expression of many immune modulatory agents, we will use targeted array screening to characterize the transcriptional responses induced by NF-kB during infection of human renal cells, focusing on those pro-inflammatory cytokines. In addition, preliminary studies show that small molecule inhibitors of NF-kB, as well as TNF receptor blockade (a likely upstream stimulatory signaling) suppress NF-kB activation in infected renal cells. Given these observations, we will test in a transgenic mouse model of HIVAN if NF-kB inhibitors or TNF receptor blockade suppresses inflammation and ameliorates renal disease progression. Defining mechanisms and pathologic sequelae of NF-kB dysregulation will identify novel treatment targets for HIVAN and other glomerulopathies characterized by pathogenic proliferation or inflammation. ? ? ?
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| Prakash, Sindhuri; Papeta, Natalia; Sterken, Roel et al. (2011) Identification of the nephropathy-susceptibility locus HIVAN4. J Am Soc Nephrol 22:1497-504 |
| Bruggeman, Leslie A; Drawz, Paul E; Kahoud, Nicole et al. (2011) TNFR2 interposes the proliferative and NF-ýýB-mediated inflammatory response by podocytes to TNF-ýý. Lab Invest 91:413-25 |
| Bruggeman, Leslie A (2009) Insight versus Quagmire with compound HIV transgenics. J Am Soc Nephrol 20:2085-6 |
| Nelson, Peter J; Bruggeman, Leslie A (2009) Collapsing glomerulopathy: beyond serendipity in mouse genetics. Kidney Int 75:353-5 |
| Bruggeman, Leslie A; Bark, Charles; Kalayjian, Robert C (2009) HIV and the Kidney. Curr Infect Dis Rep 11:479-85 |
| Bruggeman, Leslie A; Nelson, Peter J (2009) Controversies in the pathogenesis of HIV-associated renal diseases. Nat Rev Nephrol 5:574-81 |
| Bruggeman, Leslie A (2007) Viral subversion mechanisms in chronic kidney disease pathogenesis. Clin J Am Soc Nephrol 2 Suppl 1:S13-9 |
| Bruggeman, Leslie A; Martinka, Scott; Simske, Jeffrey S (2007) Expression of TM4SF10, a Claudin/EMP/PMP22 family cell junction protein, during mouse kidney development and podocyte differentiation. Dev Dyn 236:596-605 |
| Lakhe-Reddy, Sujata; Khan, Shenaz; Konieczkowski, Martha et al. (2006) Beta8 integrin binds Rho GDP dissociation inhibitor-1 and activates Rac1 to inhibit mesangial cell myofibroblast differentiation. J Biol Chem 281:19688-99 |
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