TLR2 Activation Enhances Inflammatory Signaling and Accelerates Cyst Growth and Renal Fibrosis in Polycystic Kidney Disease Mice

Authors

• Aiping Wei, Jiangxi Medical College
• Yang Zhang, Jiangxi Medical College
• Yu Xu, Jiangxi Medical College
• Jaden Schneider, Michigan Technological UniversityFollow
• Nicholas Detterman, Michigan Technological UniversityFollow
• Xiaoyun Shu, Jiangxi Medical College
• Tyler Gregersen, Michigan Technological UniversityFollow
• Maximo Nahas Folch, Michigan Technological UniversityFollow
• Yong Li, Jiangxi Medical College
• Shibiao Chen, Jiangxi Medical College
• Yan Zhang, Michigan Technological UniversityFollow

Document Type

Article

Publication Date

4-26-2026

Department

Department of Biological Sciences

Abstract

Polycystic kidney disease (PKD), the most common inherited kidney disorder, is characterized by progressive cyst growth and eventual organ failure. Although aberrant innate immune activation is a recognized contributor to PKD progression, the underlying molecular mechanisms remain incompletely defined. Here, we showed that Pkd1 deletion increased TLR2 and MyD88 mRNA expression in renal epithelial cells, indicating enhanced innate immune priming. In vivo, administration of Pam3CSK4 (PAM), a synthetic TLR2 agonist, preferentially amplified pro-inflammatory and pro-fibrotic responses in Pkd1^RC/RC mice compared with wild-type controls, despite inducing similar signaling responses in vitro. Acute PAM treatment for one week rapidly enhanced NF-κB activation in cyst-lining epithelial cells, increased renal inflammation and cell proliferation, and was associated with activation of mTOR signaling and upregulation of c-Myc and Wnt proteins. Sustained PAM treatment further accelerated cyst expansion and renal fibrosis in PKD mice. Importantly, the endogenous TLR2 ligands decorin and biglycan were markedly elevated in human PKD kidneys, supporting the translational relevance of enhanced TLR2 signaling in disease progression. Together, these findings suggest that TLR2 signaling is an important contributor to PKD progression and a potential therapeutic target.

Publisher's Statement

Copyright: © 2026 by the authors. Licensee MDPI, Basel, Switzerland. Publisher’s version of record: https://doi.org/10.3390/ijms27093853

Publication Title

International Journal of Molecular Sciences

Recommended Citation

Wei, A., Zhang, Y., Xu, Y., Schneider, J., Detterman, N., Shu, X., Gregersen, T., Folch, M., Li, Y., Chen, S., & Zhang, Y. (2026). TLR2 Activation Enhances Inflammatory Signaling and Accelerates Cyst Growth and Renal Fibrosis in Polycystic Kidney Disease Mice. International Journal of Molecular Sciences, 27(9). http://doi.org/10.3390/ijms27093853
Retrieved from: https://digitalcommons.mtu.edu/michigantech-p2/2638

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This work is licensed under a Creative Commons Attribution 4.0 International License.

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