Abstract: SA-PO989
HIV-Associated Nephropathy (HIVAN) Phenotype Is a Consequence of Compromised Parietal Epithelial Trans-Differentiation in the APOL1 Renal Risk Milieu
Session Information
- Glomerular Diseases: Podocyte Biology - II
November 04, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1403 Podocyte Biology
Authors
- Kumar, Vinod, Post Graduate Institute of Medical Education and Research, Chandigarh, Chandigarh, India
- Malhotra, Ashwani, Northwell Health Feinstein Institutes for Medical Research, Manhasset, New York, United States
- Skorecki, Karl, Bar-Ilan University, Ramat Gan, Tel Aviv, Israel
- Singhal, Pravin C., Northwell Health Feinstein Institutes for Medical Research, Manhasset, New York, United States
Background
HIV-infected patients with African ancestry carrying APOL1 variants (ARRVs G1 and G2) have a several-fold higher risk of developing HIVAN than patients with APOL1 wild-type (G0). HIV enhances APOL1 expression in parietal epithelial cells (PECs). We hypothesized that HIV-mediated PECs’ proliferation and transition are compromised in the ARRV milieu & result in PECs’ accumulation in Bowman's space, manifesting HIVAN phenotype (a collapsing variant).
Methods
The cultured human parietal epithelial cells (PECs) were transduced with vector, G0, G1 & G2 & analyzed for their proliferative, fibrotic, & podocyte (PD)-specific differentiation phenotype (transition markers) using western blotting (WB). For phenotype-specific proliferative, profibrotic, and transition markers under the HIV milieu, V/G0/G1/G2-PECs were transduced with HIV(NL4-3) for 48hr(n=4) & analyzed by WB. The expression of mTOR signaling and PECs’ transition markers was measured using Western blotting and miR193a expression by RT-PCR to evaluate the involved mechanisms. Renal tissues from control & Tg26 (a HIVAN model) mice were analyzed for miR193a & mTOR expression by FISH & IHC in PECs.
Results
In vitro studies, G1/G2-PECs displayed an increased expression of profibrotic (CD44, PERK, α-SMA, Fibronectin, Vimentin, MMP9, SNAIL) but an attenuated expression of transition markers in control and HIV milieus when compared to G0-PECs; in contrast, G0-PECs showed attenuated expression of profibrotic but an enhanced expression of transition markers in HIV milieu. These findings indicate that PEC to PD transition is compromised in G1/G2-PECs in the control and HIV milieu. G1/G2-PECs also displayed increased expression of p-mTOR,p-70S6K,p-4EBP, & p-eEF, indicating the activation of mTOR signaling. Renal cortical sections of Tg26 mice showed an increased accumulation of PECs in their Bowman's space and increased miR193a & mTOR expression by PECs compared to control mice.
Conclusion
HIVAN phenotype (collapsing variant) results from the compromised transition in profibrotic PECs to podocytes in APOL1 renal risk (G/G2) milieu in HIV-infected patients.
Funding
- NIDDK Support