Profibrotic epithelial phenotype: a central role for MRTF and TAZ

Area of Science:

• Cell Biology
• Renal Physiology
• Molecular Mechanisms of Disease

Background:

• Epithelial injury initiates fibrosis, but the epithelium does not undergo widespread epithelial-mesenchymal transition (EMT/EMyT).
• Instead, it adopts a Profibrotic Epithelial Phenotype (PEP), characterized by fibrogenic cytokine production.
• The transcriptional regulation of PEP remains largely undefined.

Purpose of the Study:

• To investigate the role of RhoA/cytoskeleton-regulated transcriptional coactivators, Myocardin-related transcription factor (MRTF) and TAZ, in mediating the Profibrotic Epithelial Phenotype (PEP).

Main Methods:

• Mechanical stress (cyclic stretch) applied to LLC-PK1 tubular cells.
• siRNA-mediated silencing and pharmacological inhibition of MRTF (CCG-1423) and TAZ (verteporfin).
• Murine model of unilateral ureteral obstruction (UUO) to induce kidney fibrosis.
• Laser capture microdissection to isolate specific cell types.

Main Results:

• Mechanical stress increased TGFβ1, CTGF, and other fibrogenic cytokine mRNA in tubular cells.
• Inhibition of MRTF or TAZ, or RhoA, mitigated these stress-induced responses.
• UUO induced tubular RhoA activation, MRTF/TAZ nuclear accumulation, and cytokine transcription specifically in the tubular epithelium.
• CCG-1423 suppressed renal and tubular expression of these fibrogenic proteins.

Conclusions:

• MRTF regulates epithelial TAZ expression.
• Both MRTF and TAZ are critical mediators of PEP-related epithelial cytokine production.
• Targeting MRTF and TAZ may offer therapeutic strategies for kidney fibrosis.