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Abstract: PO1983

Hepatocyte Growth Factor-Induced Activation of NEPHRIN and NEPH1 Serves as a Novel Mechanism for Recovery of Podocytes from Injury

Session Information

  • Podocyte Biology
    October 22, 2020 | Location: On-Demand
    Abstract Time: 10:00 AM - 12:00 PM

Category: Glomerular Diseases

  • 1204 Podocyte Biology

Authors

  • Solanki, Ashish K., Medical University of South Carolina, Charleston, South Carolina, United States
  • Srivastava, Pankaj, Medical University of South Carolina, Charleston, South Carolina, United States
  • Arif, Ehtesham, Medical University of South Carolina, Charleston, South Carolina, United States
  • Wen, Pei, University of Baltimore, Baltimore, Maryland, United States
  • Rahman, Bushra, Medical University of South Carolina, Charleston, South Carolina, United States
  • Fitzgibbon, Wayne R., Medical University of South Carolina, Charleston, South Carolina, United States
  • Lipschutz, Joshua H., Medical University of South Carolina, Charleston, South Carolina, United States
  • Holzman, Lawrence B., Medical University of South Carolina, Charleston, South Carolina, United States
  • Kwon, Sang-Ho, Augusta University, Augusta, Georgia, United States
  • Lobo, Glenn P., Medical University of South Carolina, Charleston, South Carolina, United States
  • Han, Zhe, University of Baltimore, Baltimore, Maryland, United States
  • Lazzara, Matthew J., University of Virginia, Charlottesville, Virginia, United States
  • Nihalani, Deepak, Medical University of South Carolina, Charleston, South Carolina, United States
Background

Podocytes (podo.) and their slit diaphragm(SD) are critical components of glomerular filtration barrier, whose dysfunction leads to ESRD (end stage renal disease). Treating ESRD remains a global challenge due to our poor understanding of the mechanisms that participate in recovery of podo. from injury. Glomerular injuries commonly induce podo. cell death and loss of SD, which is a modified tight junction and is constructed through a trans-interaction between the extracellular domains of NEPHRIN and NEPH1 that maintain its structural integrity. Here, we present a novel concept showing that apart from structural organization, NEPHRIN and NEPH1 constitute a receptor-based function, and can be activated in a ligand-induced fashion.

Methods

Proteomics, SPR, Immunofloroscence

Results

The ability of NEPHRIN and NEPH1 to interact with tyrosine phosphatase SHP-2 in a phosphorylation (phos.) dependent manner prompted us to investigate whether ligands that induce PTPN11 stimulation also induced activation of NEPHRIN and NEPH1. Ligands screening identified HGF as a prominent inducer of both NEPHRIN and NEPH1 phos. To further establish HGF as a ligand, we used baculovirus system to generate purified NEPHRIN and NEPH1 proteins and confirmed not only a direct interaction between HGF and the extracellular domains of NEPHRIN and NEPH1, but also, the ligand-induced phos. of these proteins. In addition to their ligand-induced activation, we demonstrate that SHP-2 can directly dephos. these proteins, thus presenting for the first time activation and deactivation mechanism for these proteins. Since HGF has a protective role in podo. and NEPHRIN and NEPH1 phos. participates in actin cytoskeletal reorganization, we hypothesize that HGF-induced activation of these proteins is critical for recovery of podo. from injury. We demonstrate that while HGF treatment repaired cultured podo. or nephrocytes in Drosophila that were injured by protamine sulphate, addition of inhibitory NEPHRIN or NEPH1 peptides that bind HGF, significantly attenuated this recovery.

Conclusion

We provide compelling evidence for the first time that HGF is a novel ligand and can stimulate signaling of slit diaphragm proteins NEPHRIN and NEPH1 in podocytes

Funding

  • NIDDK Support