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TYRO3 agonist as therapy for glomerular disease.
Fang Zhong1, Hong Cai1,2, Jia Fu1
1Department of Medicine/Nephrology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
JCI Insight
|December 1, 2022
Summary
A new compound, C-10, selectively activates TYRO3 to protect podocytes from injury. This TYRO3 agonist shows promise as a novel therapy for glomerular diseases like FSGS and DKD.
Area of Science:
- Nephrology
- Molecular Biology
- Pharmacology
Background:
- Podocyte injury and loss are central to glomerular diseases, including focal segmental glomerulosclerosis (FSGS) and diabetic kidney disease (DKD).
- Protein S (PS) and its receptor TYRO3 have demonstrated renoprotective effects through antiapoptotic and anti-inflammatory signaling in podocytes.
- TYRO3 expression is specific to podocytes, and its reduced levels correlate with glomerular disease severity in humans.
Purpose of the Study:
- To investigate the therapeutic potential of selective TYRO3 agonists for glomerular diseases.
- To develop a TYRO3-specific compound that avoids the anticoagulant activity of Protein S.
Main Methods:
- Screening of small-molecule compounds for selective TYRO3 activation.
- Characterization of compound 10 (C-10) for TYRO3 binding and selectivity against other TAM receptors (AXL, MER).
- In vivo evaluation of C-10 in mouse models of Adriamycin-induced nephropathy and type 2 diabetes (db/db), including studies in Tyro3-knockout mice.
Main Results:
- Compound 10 (C-10) selectively activated TYRO3 without affecting AXL or MER and directly bound to TYRO3.
- In vivo, C-10 significantly reduced proteinuria, glomerular injury, and podocyte loss in disease models.
- The renoprotective effects of C-10 were abolished in Tyro3-knockout mice, confirming its mechanism of action.
Conclusions:
- C-10 is a selective TYRO3 agonist that mitigates podocyte injury and glomerular disease progression.
- Targeting TYRO3 with agonists like C-10 represents a potential new therapeutic strategy for glomerular diseases.
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