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Abstract: FR-OR056

TYRO3 Is a Novel Podocyte Protective Factor in Glomerular Disease

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Zhong, Fang, Icahn Medical School at Mount Sinai, New York, New York, United States
  • Ju, Wenjun, University of Michigan, Ann Arbor, Michigan, United States
  • Kretzler, Matthias, U.Michigan, Ann Arbor, Michigan, United States
  • Lee, Kyung, Icahn School of Medicine at Mount Sinai, New York, New York, United States
  • He, John Cijiang, Mount Sinai School of Medicine, New York, New York, United States
Background

Our previous work demonstrated a protective role of protein S against podocyte loss in early diabetic kidney disease (DKD) [Zong F JASN 2018]. Protein S is known to have anti-inflammatory and anti-apoptotic effects through the activation of Tyro3, Axl, and Mer (TAM) receptors. We find that the biological effects of protein S in DKD are largely mediated by Tyro3 in podocytes. The aim of this study was to determine the role of Tyro3 in podocyte injury in glomerular disease.

Methods

Tyro3 mRNA levels were checked in different datasets of human kidneys with DKD. Tyro3 knockout mice and control WT mice were made diabetes or injected with adriamycin to induce nephropathy. Inducible podocyte-speciifc Tyro3 overexpression mice were generated and crossed with OVE26 diabetic mice or Tg26 mice or induced nephropathy with adriamycin. Albuminuria, kidney histology, and podocyte number were assessed in these mice. Western blot and PCR analysis were used to assess mechanisms of Tryo3 regulation and biological effects in cultured human podocytes.

Results

TYRO3 mRNA expression is highly enriched in human glomeruli, and immunostaining showed that TYRO3 co-localized with podocyte marker. Glomerular TYRO3 mRNA expression was suppressed in the progressive DKD. It was also suppressed in focal segmental glomerulosclerosis (FSGS). We showed that genetic ablation of Tyro3 in murine models of DKD and Adriamycin-induced nephropathy (ADRN) worsened albuminuria and glomerular injury, suggesting a protective effect of TYRO3 in early DKD and FSGS. Conversely, we showed that induction of TYRO3 overexpression specifically in podocytes significantly attenuated albuminuria and kidney injury in mice with DKD, ADRN and HIV-associated nephropathy. Mechanistically, we found that TYRO3 expression was suppressed by activation of TNF-α/NF-κB pathway, which may contribute to decreased TYRO3 expression in progressive DKD and FSGS, and TYRO3 confers anti-apoptotic effects through the activation of AKT pathway in podocytes.

Conclusion

In conclusion, we demonstrate that TYRO3 has a critical role to maintain normal podocyte function and could be a potential new drug target to treat glomerular disease.

Funding

  • NIDDK Support