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Kidney Week

Abstract: PO1819

Role of SIRT1 in HIV-Associated Kidney Disease

Session Information

Category: Glomerular Diseases

  • 1202 Glomerular Diseases: Immunology and Inflammation

Authors

  • Wang, Xuan, Department of Medicine, Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, New York, United States
  • Zhang, Weijia, Department of Medicine, Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, New York, United States
  • Klotman, Paul E., Division of Nephrology, Department of Medicine, Baylor College of Medicine, Houston, Texas, United States
  • Lee, Kyung, Department of Medicine, Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, New York, United States
  • He, John Cijiang, Department of Medicine, Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, New York, United States
Background

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 previously showed that the acetylation and activation of key inflammatory regulators, NF-κB p65 and STAT3 were increased in HIVAN kidneys. Here, we examined the key role of SIRT1 deacetylase in regulation of NF-κB and STAT3 in HIVAN.

Methods

We analyzed expression of SIRT1 in glomeruli of human and mouse HIVAN kidneys, and then we explore the role of SIRT1 on acetylation of NF-κB p65 and STAT3 and expression of HIV genes by overexpression or knock-down of SIRT1 or using SIRT1 agonist, BF175 in cultured podocytes. In vivo, we examined the effects of SIRT1 on HIVAN progression by administration of BF175 for four weeks and inducible podocyte-specific SIRT1 overexpression in Tg26. We also assessed whether miR34a was associated with SIRT1 expression.

Results

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-κB p65 and STAT3 in cultured podocytes. Interestingly, SIRT1 overexpression in turn reduced the expression of Nef in podocytes stably expressing the HIV-1 proviral genes, which was associated with the inactivation of NF-κB p65 and reduction in the HIV-1 LTR promoter activity. In vivo, the administration of small molecule SIRT1 agonist BF175 or inducible overexpression of SIRT1 specifically in podocytes markedly attenuated albuminuria and kidney lesions in Tg26 mice. Finally, the reduction in SIRT1 expression by HIV-1 is in part mediated through miR-34a expression.

Conclusion

These findings 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.

Funding

  • NIDDK Support