Abstract: FR-PO218

TAM Receptor TYRO3 Plays a Role in Pococyte Injury

Session Information

Category: Cell Biology

  • 202 Apoptosis, Proliferation, Autophagy, Cell Senescence, Cell Transformation

Authors

  • zhang, liwen ?, National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing China, Nanjing, China
  • Chen, Zhao-hong, National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing China, Nanjing, China
  • Hou, Qing, National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing China, Nanjing, China
  • Wang, Ling, National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing China, Nanjing, China
  • Li, Zhi, National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing China, Nanjing, China
  • Qin, Wei-song, National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing China, Nanjing, China
  • Liu, Zhi-Hong, National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing China, Nanjing, China
Background

Podocyte injury plays a critical role in the development and progress of diabetic nephropathy (DN). Analyzing transcriptional profile of renal biopsy from diabetic nephropathy patients and control donors identified TYRO3, a member transmembrane receptor kinase receptor (TAM), as one of the main hub genes that are strongly associated with proteinuria in type 2 DN patients. TAM receptors have been shown to play roles in immune homeostasis, neuronal differentiation and survival.

Methods

Colocalization studies detected TYRO3 protein along with the podocyte marker synaptopodin in glomeruli.

Results

No colocalization was observed between TYRO3 and endothelial marker (CD31). IHC demonstrated TYRO3 and phosphorylated TYRO3 were downregulated in the glomeruli from DN patients and db/db mice. Knockdown of tyro3 by ATG or splicing morpholino-oligos (MO) in zebrafish larvae exhibited edema (36.23%) and foot-process effacement. Permeability studies in these zebrafish morphants demonstrated disruption of the selective glomerular permeability filter. Rescue experiment showed that zebrafish co-injected with synthetic zebrafish tyro3 mRNA and MO were morphologically normal in terms of edema and foot process. While, zebrafish injected with MO of mertk, another TAM member, didn’t exhibit abnormal morphology. in vitro studies showed that podocyte express TYRO3 and its ligand GAS6. High-glucose downregulated TYRO3 mRNA and protein expression in podocytes. Moreover, depletion of TYRO3 expression with siRNAs induced and augmented high glucose induced podocytes apoptosis via PI3K/AKT /Bax/Bcl-2 pathway.

Conclusion

Taken together, our findings demonstrated that TYRO3 is a novel protein that might play a crucial role in podocyte homeostasis via stabilizing PI3K-AKT signal pathway.