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Kidney Week

Abstract: FR-PO1026

APOL1 (G0) Confers Protection from HIVAN by Facilitating Parietal Epithelial Cell (PEC) Transition to Podocytes (PD)

Session Information

Category: Genetic Diseases of the Kidney

  • 1002 Genetic Diseases of the Kidney: Non-Cystic

Authors

  • Kumar, Vinod, Fienstine Institute for Medical Research, NEW YORK, New York, United States
  • Paliwal, Nitpriya, Feinstein Institute for Medical Research, Jersey city, New Jersey, United States
  • Lan, Xiqian, Feinstein Institute for Medical Research, Jersey city, New Jersey, United States
  • Ayasolla, Kamesh R., Feinstein Institute for Medical Research, Jersey city, New Jersey, United States
  • Marashi Shoshtari, Seyedeh Shadafarin, The Feinstein Institute for Medical Research, Manhasset, New York, United States
  • Chowdhary, Sheetal, Feinstein Institute of Medical Research, New Hyde Park, New York, United States
  • Malhotra, Ashwani, Feinstein Institute Medical Research and NSLIJ, MANHASSET, New York, United States
  • Meyer-Schwesinger, Catherine, University of Hamburg, Hamburg, Germany
  • Skorecki, Karl, Rambam Health Care Campus, Haifa, Israel
  • Singhal, Pravin C., North Shore LIJ Health System, Great Neck, New York, United States
Background

The majority of HIV infected Africans carrying APOL1 risk alleles develop HIVAN if not treated with antiviral therapy. On the contrary, HIV infected Africans as well as Caucasians carrying APOL1 wild-type (G0), rarely develop HIVAN. We hypothesize that APOL1G0 facilitates PDs renewal by PECs, thus allowing replenishment of HIV-induced podocyte loss, whereas, PECs expressing APOL1G1 or APOL1G2 are not able to complete the transition and accumulate into Bowman’s space.

Methods

To aim transition (differentiation) to PDs, immortalized human PECs were incubated in special media for 14 days. PEC- transduced with either Vector or HIV (NL4-3) were assayed for APOL1 expression. To determine the role of APOL1, differentiated PECs were transduced with Vector, APOL1G0, APOL1G1, or APOL1G2 lentivirus. After 48 hours, cellular lysates were probed PEC (PAX2 and Claudin 1) and PD (CD2AP, WT1, α-actinin, and podocalyxin) markers. To determine the role of APOL1-miR193a axis, cellular lysates of above-mentioned transduced cells were assayed for miR193a expression and PEC/PD markers. To confirm the disruption of APOL1-miR193a axis, HEKs (human embryonic kidney cells with undetectable APOL1 expression) were transfected with Vector, APOL1G0, APOL1G1, or APOL1G2 plasmids followed by evaluation of miR193a expression and PEC/PD markers. Human renal biopsy specimens and renal cortical sections of 4-week and 8-week old HIV transgenic mice (Tg26) expressing APOL1G0, APOL1G1, and APOL1G2 were graded for the severity of renal lesions.

Results

HIV induced the expression of APOL1 in PECs. The induction of APOL1 in undifferentiated PECs and HEKs down-regulated miR193a expression but stimulated the expression of PD markers. APOL1G1 and APOL1G2 in differentiated PDs as well as in differentiated PECs down-regulated PD markers but upregulated the expression of miR193a. Renal biopsy specimens of HIVAN patients displayed accumulation of PECs in Bowman’s space with the expression of occasional PD markers. Tg26: APOL1G0 mice displayed minimal accumulation of PECs in Bowman’s space as well as minimal renal lesions vs. TG26: APOL1 G1/G2 mice.

Conclusion

APOL1G0 prevents the development of HIVAN through facilitating PECs transition to PDs.

Funding

  • NIDDK Support