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Abstract: FR-PO157

Vitamin D Receptor (VDR) Expression Determines Initiation and Progression of Renal Lesions in HIV-Transgenic Mice with Variable Angiotensinogen (Agt) Copies

Session Information

Category: Glomerular Diseases

  • 1201 Glomerular Diseases: Fibrosis and Extracellular Matrix

Authors

  • Vashistha, Himanshu, Ochsner Health System, New Orleans, Louisiana, United States
  • Kumar, Vinod, Fienstine Institute for Medical Research, NEW YORK, New York, United States
  • Lan, Xiqian, Feinstein Institute for Medical Research, Manhasset, New York, United States
  • Malhotra, Ashwani, Feinstein Institute Medical Research and NSLIJ, MANHASSET, New York, United States
  • Singhal, Pravin C., North Shore LIJ Health System, Great Neck, New York, United States
Background

Agt transgenic mice have been shown to carry higher serum and cellular levels of Angiotensin II levels and associated downstream effects. Since Ang II has been shown to play a role in the progression of HIVAN, we hypothesized that mice with enhanced expression of Agt would display a rapid progression of renal lesions in a mouse model of HIVAN. We evaluated the effect of different copies of Agt in the initiation and progression of HIVAN in genetically engineered HIVAN mice (Tg26) expressing variable copies of Agt.

Methods

Control and Tg26 mice with 2 (Tg26/Agt-2) and 4 (Tg26/Agt-4) copies of Agt were evaluated for severity of renal lesions, arteriosclerosis and hypertension at 8 weeks and 16 weeks. Renal cortical sections were stained with Sirus red and PAS. RNA was extracted from renal tissues and probed for AT1, AT2, VDR, and molecules involved in profibtotic and epithelial-mesenchymal transition (EMT) pathways. Renal lesions were graded for their severity.

Results

Tg26/Agt-4/8wks showed lower blood pressure (P<0.01) vs. Tg26/Agt-2/8 wks, while Tg26/Agt-4/16wks displayed higher blood pressure vs. Tg26/Agt-2/16wks. Tg26/Agt-4/8wks displayed attenuated expression of PAI-1 vs. Tg26/Agt-2/8wks; however, Tg26/Agt-4/16wks showed 3-fold greater PAI-1 expression than to Tg26/Agt-2/16wks. Tg26/Agt-2/8wks displayed attenuated expression of VDR and enhanced production of Ang II vs. Tg26/Agt-4/8wks; however, this pattern reversed at 16 wks. Tg26/Agt-4/8wks displayed attenuated expression of AT1 and AT2 and down-regulation of Tert, TGF-β, Snail, and vimentin when compared to Tg26/Agt-2/8wks. Nonetheless, all these markers were comparable between these groups at 16 wk of age. Tg26/Agt-2/8wks developed renal lesions which were more advanced than Tg26/Agt-4/8wks. Conversely, Tg26/Agt-4/16wks displayed more advanced renal lesions vs. Tg26/Agt-2/16wks

Conclusion

Tg26/Agt-4 displayed slower progression of HIVAN initially at 8 weeks associated with enhanced renal tissue VDR expression and attenuated expression of AT1, TGB-β, PAI-1, Tert and EMT markers. However, Tg26/Agt-4 at 16 wks displayed accelerated growth due to attenuated VDR expression leading to high blood pressure, upregulation of EMT and profibrotic molecules.

Funding

  • NIDDK Support