YAP promotes AP-1 expression in tubular epithelial cells in the kidney

Area of Science:

• Nephrology
• Molecular Biology
• Cell Biology

Background:

• Chronic kidney disease (CKD) is a significant global health issue, characterized by kidney fibrosis.
• The Hippo/yes-associated protein (YAP) pathway is implicated in organ size regulation, inflammation, and cancer.
• Previous research linked tubular YAP activation to CKD, but the precise mechanisms require further elucidation.

Purpose of the Study:

• To investigate the role of YAP in regulating activator protein-1 (AP-1) expression in the kidney.
• To identify the specific AP-1 components targeted by YAP in renal tubular cells.
• To elucidate the molecular mechanisms by which YAP contributes to kidney fibrosis.

Main Methods:

• Utilized mouse models of kidney injury, including unilateral ureteric obstruction and tubule-specific Mst1/2 knockout.
• Employed genetic deletion of Yap in tubular cells to assess its impact on AP-1 component expression.
• Performed experiments in HK-2 and IMCD3 renal tubular cell lines to confirm YAP's effect on AP-1 genes.
• Investigated YAP's direct interaction with the Fosl1 promoter using luciferase reporter assays.

Main Results:

• AP-1 component expression was upregulated in kidneys with ureteric obstruction and in Mst1/2 knockout models.
• Deletion of Yap in tubular cells significantly blocked the induction of AP-1 components, particularly Fosl1.
• Inhibition of Yap in renal tubular cell lines suppressed Fosl1 expression more than other AP-1 genes.
• YAP demonstrated direct binding to the Fosl1 promoter, enhancing its transcriptional activity.

Conclusions:

• YAP activation is a key regulator of AP-1 expression in renal tubular cells.
• Fosl1 is identified as the primary target gene of YAP in the kidney.
• These findings reveal a novel mechanism by which YAP contributes to tubular injury and kidney fibrosis in CKD.