Myocardin-related transcription factor drives epithelial fibrogenesis in polycystic kidney disease

Lichner, Z.; Ding, M.; Khare, T.; Dan, Q.; Benitez, R.; Praszner, M.; Song, X.; Saleeb, R.; Hinz, B.; Pei, Y.; Szaszi, K.; Kapus, A.

doi:10.1101/2024.03.15.585204

bioRxiv · 10.1101/2024.03.15.585204

Myocardin-related transcription factor drives epithelial fibrogenesis in polycystic kidney disease

Lichner, Z.·Ding, M.·Khare, T.·Dan, Q.·Benitez, R.·Praszner, M.·Song, X.·Saleeb, R.·Hinz, B.·Pei, Y.·Szaszi, K.·Kapus, A.

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Abstract

Polycystic kidney disease (PKD) is characterized by extensive cyst formation and progressive fibrosis. However, the molecular mechanisms whereby the loss/loss-of-function of Polycystin 1 or 2 (PC1/2) provokes fibrosis are largely unknown. The small GTPase RhoA has been recently implicated in cystogenesis, and we have shown that the RhoA/cytoskeleton/myocardin-related transcription factor (MRTF) pathway is a key mediator of epithelium-induced fibrogenesis. Therefore, we hypothesized that MRTF is activated by PC1/2 loss and plays a critical role in fibrogenic reprogramming of the epithelium. Loss of PC1 or PC2 induced by siRNA in vitro activated RhoA, caused cytoskeletal remodeling and robust nuclear MRTF translocation and overexpression. These phenomena were also manifest in PKD1 (RC/RC) and PKD2 (WS25/-) mice, with MRTF translocation and overexpression occurring predominantly in dilated tubules and in cyst-lining epithelium, respectively. In epithelial cells, a large cohort of PC1/PC2 downregulation-induced genes was MRTF-dependent, including cytoskeletal, integrin-related, and matricellular/fibrogenic proteins. Epithelial MRTF was necessary for paracrine priming of fibroblast-myofibroblast transition. Thus, MRTF is a critical novel mediator of the PC1/2 loss-induced profibrotic epithelial phenotype, and consequently PKD-related fibrosis.

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Lichner, Z., Ding, M., Khare, T., Dan, Q., Benitez, R., Praszner, M., Song, X., Saleeb, R., Hinz, B., Pei, Y., Szaszi, K., Kapus, A.. 2024-03-17. Myocardin-related transcription factor drives epithelial fibrogenesis in polycystic kidney disease. https://doi.org/10.1101/2024.03.15.585204

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