Abstract: FR-PO685

Vitamin D Receptor (VDR) Agonist Slows Down Progression of HIVAN via Down Regulation of HIV Gene Expression

Session Information

Category: Glomerular

  • 1001 Glomerular: Basic/Experimental Immunology and Inflammation

Authors

  • Marashi Shoshtari, Seyedeh Shadafarin, The Feinstein Institute for Medical Research, Manhasset, New York, United States
  • Aslam, Rukhsana, Feinstein Institute for medical research, Glenoaks, New York, United States
  • Kumar, Vinod, The Feinstein Institute for Medical Research, Manhasset, New York, United States
  • Malhotra, Ashwani, Feinstein Institute for medical research, Glenoaks, New York, United States
  • Singhal, Pravin C., North Shore LIJ Health System, Great Neck, New York, United States
Background

Activation of renin angiotensin system (RAS) has been demonstrated to play an important role for the progression of HIVAN. This effect of RAS has been attributed to modulation of hemodynamic factors as well as direct cytotoxicity to kidney cells. We have previously demonstrated that HIV enhances kidney cell renin expression. We now hypothesize that renin enhances HIV gene expression and this effect of renin could be prevented by VDR agonist, resulting in slowing down the progression of HIVAN.

Methods

Human podocytes (HPs) were transdudced with either vector (V/HP) or HIV (NL4-3, HIV/HP). To increase endogenous renin production, V/HPs and HIV/HPs were transfected with siRNA vitamin D receptor (siRNA-VDR/HIV/HPs) or scrambled (Scr-siRNA/HIV/HP) siRNA; protein blots were probed for renin and actin expressions. To evaluate the effect of renin in vivo, mRNA expressions of HIV genes from renal tissues of HIVAN (Tg26) mice with higher endogenous renin (Tg26 mice expressing 2, 3 and 4 copies of angiotensinogen [Agt] or lacking VDR) were quantified by qPCR. To down regulate renal tissue renin expression, Tg26 mice were treated with either vehicle or a VDR agonist (VDA) for 2 weeks and renal tissues were evaluated for HIV gene expression. In addition, gene expression and progression of renal lesions in Tg26 mice, Tg26 mice lacking renin, and Tg26 mice treated with VDA. were compared.

Results

HIV enhanced renin expression in HPs. Silencing of VDR in HIV/HPs further enhanced expression of Nef, Tat, and Vif. However, VDA down regulated HIV gene expression in HIV/HPs. Renal tissues of Tg26 with 4 Agt copies displayed 2-4 fold increase in mRNA expression of gp120, Vpr, Tat, Nef and Vpu vs. Tg26 (Agt 2 copies). Similarly, Tg26 mice lacking VDR displayed greater HIV gene expression when compared to Tg26 mice with intact VDR. VDA-treated of Tg26 mice not only down regulated renal tissue expressions of renin but also attenuated expression of HIV genes. Tg26 mice lacking renin or treated with VDA, displayed attenuated renal tissue HIV gene expression and slowed down the rate of progression of renal lesions.

Conclusion

Renin enhances renal tissue and podocyte HIV gene expression and induces accelerated progression of renal lesions; however, this effect of renin could be prevented by VDA treatment.

Funding

  • NIDDK Support