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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Program Projects (P01)
Project #
2P01DK056492-17A1
Application #
9204217
Study Section
Special Emphasis Panel (ZDK1-GRB-1 (M6)P)
Project Start
Project End
Budget Start
2016-08-01
Budget End
2017-07-31
Support Year
17
Fiscal Year
2017
Total Cost
$305,541
Indirect Cost
$33,388
Name
Baylor College of Medicine
Department
Type
Domestic Higher Education
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Chan, Lili; Asriel, Benjamin; Eaton, Ellen F et al. (2018) Potential kidney toxicity from the antiviral drug tenofovir: new indications, new formulations, and a new prodrug. Curr Opin Nephrol Hypertens 27:102-112
Swanepoel, Charles R; Atta, Mohamed G; D'Agati, Vivette D et al. (2018) Kidney disease in the setting of HIV infection: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. Kidney Int 93:545-559
Zhong, Fang; Chen, Zhaohong; Zhang, Liwen et al. (2018) Tyro3 is a podocyte protective factor in glomerular disease. JCI Insight 3:
Palau, Laura; Menez, Steven; Rodriguez-Sanchez, Javier et al. (2018) HIV-associated nephropathy: links, risks and management. HIV AIDS (Auckl) 10:73-81
Zhong, Fang; Chen, Haibing; Xie, Yifan et al. (2018) Protein S Protects against Podocyte Injury in Diabetic Nephropathy. J Am Soc Nephrol 29:1397-1410
Hong, Quan; Zhang, Lu; Das, Bhaskar et al. (2018) Increased podocyte Sirtuin-1 function attenuates diabetic kidney injury. Kidney Int 93:1330-1343
Fu, Jia; Wei, Chengguo; Zhang, Weijia et al. (2018) Gene expression profiles of glomerular endothelial cells support their role in the glomerulopathy of diabetic mice. Kidney Int 94:326-345
Corona-Villalobos, Celia P; Shlipak, Michael G; Tin, Adrienne et al. (2017) Predictors of Acute Renal Injury Study (PARIS) among HIV-positive individuals: design and methods. BMC Nephrol 18:289
Gu, Xiangchen; Mallipattu, Sandeep K; Guo, Yiqing et al. (2017) The loss of Krüppel-like factor 15 in Foxd1+ stromal cells exacerbates kidney fibrosis. Kidney Int 92:1178-1193
Wei, Chengguo; Li, Li; Menon, Madhav C et al. (2017) Genomic Analysis of Kidney Allograft Injury Identifies Hematopoietic Cell Kinase as a Key Driver of Renal Fibrosis. J Am Soc Nephrol 28:1385-1393

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