Abstract: SA-PO235
Tyro3 Agonist as a Novel Therapy for Glomerular Disease
Session Information
- Diabetic Kidney Disease: Basic - II
November 05, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
Abstract Time: 10:00 AM - 12:00 PM
Category: Diabetic Kidney Disease
- 601 Diabetic Kidney Disease: Basic
Authors
- Zhong, Fang, Icahn School of Medicine at Mount Sinai, New York, New York, United States
- Cai, Hong, Icahn School of Medicine at Mount Sinai, New York, New York, United States
- Lee, Kyung, Icahn School of Medicine at Mount Sinai, New York, New York, United States
- He, John Cijiang, Icahn School of Medicine at Mount Sinai, New York, New York, United States
Background
Drugs directly targeting podocytes as a therapy for glomerular disease are still lacking. Our previous studies suggest that Tyro3 is a podocyte-specific TAM (Tyro3, Axl, MertK) tyrosine kinase receptor. In human, glomerular Tyro3 expression negatively correlates with the progression of primary glomerular disease and diabetic kidney disease (DKD). Knockout of Tyro3 aggravates podocyte injury in Adriamycin-induced nephropathy (ARDN) and DKD mice while induction of Tyro3 expression in podocytes ameliorates kidney injury in these two animal models,. These data suggest a protective role of Tyro3 against podocyte injury in glomerular disease. Here, we liked to further dissect the mechanisms of Tyro3 in podocytes and develop Tyro3 agonists as potential drugs to treat glomerular disease.
Methods
In vitro studies: culture of human podocytes with overexpression or knockdown of Tyro3, western blot, co-immunosprecipitation, and mass spectrometry. In vivo studies: OVE26 diabetic mice and ARDN treated with Tyro3 agonists or vehicle. Kidney histology, albuminuria, and renal function will be assessed in these mice.
Results
By immunoprecipitation combined with mass spectrometry analysis we identified TCTP and nicalin as the top Tyro3-interacted proteins. Nicalin is a member of the γ-secretase complex. TCTP is known to inhibit apoptosis through interaction with multiple partners such as p53 and Bax. We showed that Tyro3 interacted with TPTC to induce its phosphorylation and thereby inhibiting apoptosis of podocytes. Tyro3 also interacted with nicalin to induce the cleavage of Tyro3 into a soluble form. Overexpression of soluble Tyro3 inhibits its protective effects of Tyro3 in podocytes. Circulating Tyro3 increased in DKD patients. Therefore, our data suggest that increased soluble Tyro3 in DKD patients could suppress the protective effects of Tyro3 in podocytes, leading to more podocyte injury. In addition, we screened and identified a specific Tyro3 agonist (C10) which induced phosphorylation in Tyro3 but not in other TMA receptors. This Tyro3-specific agonist reduced apoptosis of human podocytes cultured in high glucose condition and ameliorated podocyte loss and glomerular injury in mice with ARDN and DKD.
Conclusion
In conclusion, we reveal a novel protective mechanism of Tyro3 in podocytes and develop a novel class of podocyte-specific drugs which could be potentially developed to treat glomerular disease.
Funding
- Veterans Affairs Support