Abstract: FR-PO1209
Myocardin-Related Transcription Factor (MRTF) in Kidney Fibrosis and Its Cross-Talk with Sox9
Session Information
- CKD: Mechanisms, AKI, and Beyond - 2
November 07, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2303 CKD (Non-Dialysis): Mechanisms
Authors
- Kapus, Andras, St Michael's Hospital Keenan Research Centre for Biomedical Science, Toronto, Ontario, Canada
- Lichner, Zsuzsanna A, St Michael's Hospital Keenan Research Centre for Biomedical Science, Toronto, Ontario, Canada
- Khare, Tarang, St Michael's Hospital Keenan Research Centre for Biomedical Science, Toronto, Ontario, Canada
Background
Our previous work has shown that the RhoA/F-actin-regulated transcriptional coactivator MRTF plays a key role in the pathogenesis of experimental kidney fibrosis in obstructive nephropathy and polycystic kidney disease. Indeed, MRTF is a central inducer of the profibrotic epithelial phenotype (PEP) upon tubular injury. Further, recent studies implicated Sox9 as a major driver of both kidney regeneration and fibrosis. Interestingly, myocardin, a muscle-specific relative of MRTF, and Sox9 were shown to inhibit each other in vascular smooth muscle cells. Accordingly, the goal of the current studies was twofold: We wished to 1) discern if MRTF and MRTF-inducible genes are enriched in experimental and clinical kidney disease in the tubular epithelium; 2) study the interplay between MRTF and Sox9. As fibrosis requires a switch between normal and maladaptive repair, we wondered if these two fibrogenic transcription factors might control each other’s activity.
Methods
We performed scRNASeq meta-analysis on a mouse AKI dataset, and on the human KPMP AKI and CKD databases (1). The interplay between MRTF and SOX9 was followed in tubular cells (LLC-PK1, HEK), using a variety of biochemical/transcriptional assays as indicated at the corresponding results (2).
Results
1) In AKI, MRTF and its targets (e.g. Myh9, ITGB1) were enriched in injured (Kim1+) tubular cells. In human CKD, increased MRTF expression was observed in a subcompartment of the injured proximal tubular cell cluster. Importantly, the correlation among MRTF target genes differed in healthy controls vs CKD patients. In CKD, two new clusters emerged, one of which overlapped with Sox9 targets, while the other was independent.
2) Endogenous or heterologously expressed MRTF and Sox9 bound each other as shown by co-immunoprecipitation. MRTF silencing or KO increased Sox9 expression, while Sox9 had no impact on MRTF expression. Sox9 overexpression inhibited MRTF-induced transcription (SMA promoter-Luc) and SMA expression. Conversely, MRTF overexpression reduced Sox9-driven transcription (4XCol2A1-Luc).
Conclusion
Thus, enhanced tubular MRTF signaling is a significant feature in AKI and clinical CKD. Moreover, MRTF and Sox9 interact and inhibit each other’s activity in a cellular setting. The pathophysiological significance of their crosstalk in the fibrogenic epithelium requires future studies.