Role of SIRT1 in HIV-associated kidney disease

Xuan Wang, Ruijie Liu, Weijia Zhang, Deborah P. Hyink, Gokul C. Das, Bhaskar Das, Zhengzhe Li, Andrew Wang, Weijie Yuan, Paul E. Klotman, Kyung Lee, John Cijiang He

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

Human immunodeficiency virus (HIV) infection of kidney cells can lead to HIV-associated nephropathy (HIVAN) and aggravate the progression of other chronic kidney diseases. Thus, a better understanding of the mechanisms of HIV-induced kidney cell injury is needed for effective therapy against HIV-induced kidney disease progression. We have previously shown that the acetylation and activation of key inflammatory regulators, NF-KB p65 and STAT3, were increased in HIVAN kidneys. Here, we demonstrate the key role of sirtuin 1 (SIRT1) deacetylase in the regulation of NF-KB and STAT3 activity in HIVAN. We found that SIRT1 expression was reduced in the glomeruli of human and mouse HIVAN kidneys and that HIV-1 gene expression was associated with reduced SIRT1 expression and increased acetylation of NF-KB p65 and STAT3 in cultured podocytes. Interestingly, SIRT1 overexpression, in turn, reduced the expression of negative regulatory factor in podocytes stably expressing HIV-1 proviral genes, which was associated with inactivation of NF-KB p65 and a reduction in HIV-1 long terminal repeat promoter activity. In vivo, the administration of the small-molecule SIRT1 agonist BF175 or inducible overexpression of SIRT1 specifically in podocytes markedly attenuated albuminuria, kidney lesions, and expression of inflammatory markers in Tg26 mice. Finally, we showed that the reduction in SIRT1 expression by HIV-1 is in part mediated through miR-34a expression. Together, our data provide a new mechanism of SIRT1 regulation and its downstream effects in HIV-1-infected kidney cells and indicate that SIRT1/miR-34a are potential drug targets to treat HIV-related kidney disease.

Original languageEnglish
Pages (from-to)F335-F344
JournalAmerican Journal of Physiology - Renal Physiology
Volume319
Issue number2
DOIs
StatePublished - Aug 2020

Keywords

  • Activator of transcription 3
  • Human immunodeficiency virus
  • Kidney disease
  • Nuclear factor-KB
  • Podocytes
  • Signal transducer
  • Sirtuin 1

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