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Abstract: TH-PO420

Collapsing Phenotype Is a Consequence of HIV-Induced Profibrotic and Compromised Transition of Parietal Epithelial Cells in APOL1 Renal Risk Milieu

Session Information

Category: Glomerular Diseases

  • 1301 Glomerular Diseases: Fibrosis and Extracellular Matrix

Authors

  • Kumar, Vinod, Post Graduate Institute of Medical Education and Research Department of Dermatology Venereology and Leprology, Chandigarh, Chandigarh, India
  • Malhotra, Ashwani, Northwell Health Feinstein Institutes for Medical Research, Manhasset, New York, United States
  • Singhal, Pravin C., Northwell Health Feinstein Institutes for Medical Research, Manhasset, New York, United States
Background

HIV-infected patients with African ancestry carrying APOL1 renal risk alleles (ARRAs G1and G2) have a several-fold higher risk of developing HIVAN than patients having APOL1-G0. HIV induces APOL1 in parietal epithelial cells (PECs). Since the expression of APOL1 (wild-type, G0) in monocytes make them resistant to cellular injury and HIV replication, its potential in PECs in general and ARRAs, in particular, has not been investigated. We hypothesized that HIV-mediated PECs’ proliferation and the transition are compromised in the ARRAs (G1/G2) milieu & result in their accumulation in Bowman's space, manifesting collapsing phenotype.

Methods

The cultured human parietal epithelial cells (hPECs) 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 transitions 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 signalling. 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

Accumulation of PECs in Bowman’s space is a consequence of compromised transition in profibrotic PECs in APOL1 renal risk (G/G2) milieu in HIV-infected patients

Funding

  • NIDDK Support