Cargando…

TYRO3 agonist as therapy for glomerular disease

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Zhong, Fang, Cai, Hong, Fu, Jia, Sun, Zeguo, Li, Zhengzhe, Bauman, David, Wang, Lois, Das, Bhaskar, Lee, Kyung, He, John Cijiang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Clinical Investigation 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9870075/
https://www.ncbi.nlm.nih.gov/pubmed/36454644
http://dx.doi.org/10.1172/jci.insight.165207
_version_ 1784876894971232256
author Zhong, Fang
Cai, Hong
Fu, Jia
Sun, Zeguo
Li, Zhengzhe
Bauman, David
Wang, Lois
Das, Bhaskar
Lee, Kyung
He, John Cijiang
author_facet Zhong, Fang
Cai, Hong
Fu, Jia
Sun, Zeguo
Li, Zhengzhe
Bauman, David
Wang, Lois
Das, Bhaskar
Lee, Kyung
He, John Cijiang
author_sort Zhong, Fang
collection PubMed
description 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.
format Online
Article
Text
id pubmed-9870075
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher American Society for Clinical Investigation
record_format MEDLINE/PubMed
spelling pubmed-98700752023-02-06 TYRO3 agonist as therapy for glomerular disease Zhong, Fang Cai, Hong Fu, Jia Sun, Zeguo Li, Zhengzhe Bauman, David Wang, Lois Das, Bhaskar Lee, Kyung He, John Cijiang JCI Insight Research Article 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. American Society for Clinical Investigation 2023-01-10 /pmc/articles/PMC9870075/ /pubmed/36454644 http://dx.doi.org/10.1172/jci.insight.165207 Text en © 2023 Zhong et al. https://creativecommons.org/licenses/by/4.0/This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research Article
Zhong, Fang
Cai, Hong
Fu, Jia
Sun, Zeguo
Li, Zhengzhe
Bauman, David
Wang, Lois
Das, Bhaskar
Lee, Kyung
He, John Cijiang
TYRO3 agonist as therapy for glomerular disease
title TYRO3 agonist as therapy for glomerular disease
title_full TYRO3 agonist as therapy for glomerular disease
title_fullStr TYRO3 agonist as therapy for glomerular disease
title_full_unstemmed TYRO3 agonist as therapy for glomerular disease
title_short TYRO3 agonist as therapy for glomerular disease
title_sort tyro3 agonist as therapy for glomerular disease
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9870075/
https://www.ncbi.nlm.nih.gov/pubmed/36454644
http://dx.doi.org/10.1172/jci.insight.165207
work_keys_str_mv AT zhongfang tyro3agonistastherapyforglomerulardisease
AT caihong tyro3agonistastherapyforglomerulardisease
AT fujia tyro3agonistastherapyforglomerulardisease
AT sunzeguo tyro3agonistastherapyforglomerulardisease
AT lizhengzhe tyro3agonistastherapyforglomerulardisease
AT baumandavid tyro3agonistastherapyforglomerulardisease
AT wanglois tyro3agonistastherapyforglomerulardisease
AT dasbhaskar tyro3agonistastherapyforglomerulardisease
AT leekyung tyro3agonistastherapyforglomerulardisease
AT hejohncijiang tyro3agonistastherapyforglomerulardisease