Low expression of HIV genes in podocytes accelerates the progression of diabetic kidney disease in mice

Jie Feng, Li Bao, Xuan Wang, Huilin Li, Yuqiang Chen, Wenzhen Xiao, Zhengzhe Li, Liyi Xie, Wanhong Lu, Hongli Jiang, Kyung Lee, John Cijiang He

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

With the widespread use combination antiretroviral therapy, there has been a dramatic decrease in HIV-associated nephropathy. However, although the patients living with HIV have low or undetectable viral load, the prevalence of chronic kidney disease (CKD) in this population remains high. Additionally, improved survival is associated with aging-related comorbidities such as diabetes and cardiovascular disease. A faster progression of CKD is associated with concurrent HIV infection and diabetes than with HIV infection or diabetes alone. To explore the potential pathogenic mechanisms that synergistically drive CKD progression by diabetes and HIV infection, we generated a new mouse model with a relatively low expression of HIV-1 proviral genes specifically in podocytes (pod-HIV mice) to better mimic the setting of kidney injury in patients living with HIV. While no apparent kidney phenotypes were observed at baseline in pod-HIV mice, the induction of mild diabetic kidney disease with streptozotocin led to significant worsening of albuminuria, glomerular injury, podocyte loss, and kidney dysfunction as compared to the mice with diabetes alone. Mechanistically, diabetes and HIV-1 synergistically increased the glomerular expression of microRNA-34a (miR-34a), thereby reducing the expression of Sirtuin-1 (SIRT1) deacetylase. These changes were also associated with increased acetylation and activation of p53 and p65 NF-κB and with enhanced expression of senescence and inflammatory markers. The treatment of diabetic pod-HIV mice with the specific Sirtuin-1 agonist BF175 significantly attenuated albuminuria and glomerulopathy. Thus, our study highlights the reduction in Sirtuin-1 as a major basis of CKD progression in diabetic patients living with HIV and suggests Sirtuin-1 agonists as a potential therapy.

Original languageEnglish
Pages (from-to)914-925
Number of pages12
JournalKidney International
Volume99
Issue number4
DOIs
StatePublished - Apr 2021

Keywords

  • HIV infection
  • SIRT1
  • diabetic kidney disease
  • inflammation
  • podocytes

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