With the widespread use of combination antiretroviral agents, the incidence of HIV-associatednephropathy (HIVAN) has dramatically decreased in the recent years. Yet, the prevalence of chronickidney disease (CKD) and end-stage renal disease (ESRD) in HIV sero-positive patients remainshigh, suggesting that HIV-positive patients are at increased risk for a variety of acute and chronickidney diseases. Indeed, several lines of evidence from recent epidemiological and animal modelstudies indicate that concurrent HIV infection and age-related comorbidities, such as diabetesmellitus, have a synergistic effect on the incidence of chronic kidney disease, thereby necessitatingan examination of mechanisms by which HIV infection accelerates the progression of CKD such asdiabetic kidney disease (DKD). We have recently shown that the upregulation of local inflammationinduced by HIV aggravates the progression of DKD through increased transcriptional activities of NF-?B and STAT3, indicating that HIV-induced chronic inflammation may predispose and excerbate thecourse of non-HIV related CKD. We have also shown that SIRT1 histone deacetylase is a keymodulator of the transcriptional activities of NF-?B and STAT3 in diabetic kidneys, suggesting thatpro-inflammatory responses that drive CKD progression may share a common pathway. Wetherefore posit that SIRT1 is a central modulator of chronic HIV infection-induced inflammationthrough deacetylation of key transcription factors such as NF-?B and STAT3, and that the regulationof SIRT1 and NF-?B may be effective therapeutic approaches against HIV-induced CKD. Using smallmolecule agonist of SIRT1 and antagonist of NF-?B, and novel transgenic mouse models, wepropose to determine the role of SIRT1 in regulating HIV-mediated cellular injuries in diabetickidneys. Our results will provide a better understanding of the underlying molecular mechanisms bywhich chronic HIV infection accelerates the progression of CKD and a proof-of-concept for noveltarget treatment for CKD in HIV patients.
HIV-infected patients in US now live longer owing to the effective antiretroviral therapy. However; the incidenceand prevalence of chronic kidney disease leading to end-stage renal disease continues to increase in HIV-infectedindividuals; due to comorbidities such as diabetes; hypertension; and HCV. The current proposal tostudy how chronic HIV infection contributes to the progression of age-related kidney disease; such as diabetickidney disease; is highly relevant and knowledge gained will allow for development of more effective therapies.
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