TYRO3 agonist as therapy for glomerular disease
Fang Zhong, … , Kyung Lee, John Cijiang He
Fang Zhong, … , Kyung Lee, John Cijiang He
Published December 1, 2022
Citation Information: JCI Insight. 2023;8(1):e165207. https://doi.org/10.1172/jci.insight.165207.
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Research Article Nephrology

TYRO3 agonist as therapy for glomerular disease

Abstract

Podocyte injury and loss are key drivers of primary and secondary glomerular diseases, such as focal segmental glomerulosclerosis (FSGS) and diabetic kidney disease (DKD). We previously demonstrated the renoprotective role of protein S (PS) and its cognate tyrosine-protein kinase receptor, TYRO3, in models of FSGS and DKD and that their signaling exerts antiapoptotic and antiinflammatory effects to confer protection against podocyte loss. Among the 3 TAM receptors (TYRO3, AXL, and MER), only TYRO3 expression is largely restricted to podocytes, and glomerular TYRO3 mRNA expression negatively correlates with human glomerular disease progression. Therefore, we posited that the agonistic PS/TYRO3 signaling could serve as a potential therapeutic approach to attenuate glomerular disease progression. As PS function is not limited to TYRO3-mediated signal transduction but includes its anticoagulant activity, we focused on the development of TYRO3 agonists as an optimal therapeutic approach to glomerular disease. Among the small-molecule TYRO3 agonistic compounds screened, compound 10 (C-10) showed a selective activation of TYRO3 without any effects on AXL or MER. We also confirmed that C-10 directly binds to TYRO3, but not the other receptors. In vivo, C-10 attenuated proteinuria, glomerular injury, and podocyte loss in mouse models of Adriamycin-induced nephropathy and a db/db model of type 2 diabetes. Moreover, these renoprotective effects of C-10 were lost in Tyro3-knockout mice, indicating that C-10 is a selective agonist of TYRO3 activity that mitigates podocyte injury and glomerular disease. Therefore, C-10, a TYRO3 agonist, could be potentially developed as a new therapy for glomerular disease.

Authors

Fang Zhong, Hong Cai, Jia Fu, Zeguo Sun, Zhengzhe Li, David Bauman, Lois Wang, Bhaskar Das, Kyung Lee, John Cijiang He

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Figure 1

C-10 is a TYRO3 agonist.

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C-10 is a TYRO3 agonist. (A) Cultured human podocytes were treated with ...
(A) Cultured human podocytes were treated with control vehicle (C) or TYRO3 agonists (compounds 1–12) for 30 minutes. Cell lysates were probed for phosphorylated or total TYRO3 (p-TYRO3 or t-TYRO3). GAPDH was used as a loading control. (B) Cultured human podocytes were stimulated with compound 10 (C-10) for 30 minutes at different doses as indicated, and cell lysates were probed for p-TYRO3 or t-TYRO3 and for p-AKT or t-AKT. GAPDH was used as a loading control. (C) Cultured podocytes were treated with vehicle control (C), 10 μM TNF-α alone (T), or TNF-α with TYRO3 agonists (compounds 1–12) for 2 hours. Real-time PCR analysis was performed for expression of NF-κB target genes, IL6 and CCL2 (n = 3). *P < 0.05, **P < 0.01 compared with TNF-α–treated cells by 1-way ANOVA with Bonferroni’s correction.