Kidney Week

Abstract: FR-PO0235

YAP Is a Key Regulator of Renal Homeostasis and Inflammatory Injury in Nephronophthisis

Session Information

• CKD: Mechanisms of Injury and Fibrosis - 2
  October 23, 2026 | Location: Exhibit Hall A, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

• 2203 CKD (Non-Dialysis): Mechanisms

Authors

• Goffette, Valentine, Université Paris Cité, Institut Imagine, Laboratory of Hereditary Kidney Diseases, INSERM U1163, Paris, Ile-de-France, France

Valentine Goffette, PhD

• Ferri, Giulia, Université Paris Cité, Institut Imagine, Laboratory of Hereditary Kidney Diseases, INSERM U1163, Paris, Ile-de-France, France

Giulia Ferri, MSc, PhD

• Bienaime, Frank, Université Paris Cité, INSERM U1151, CNRS UMR-8253, Institut Necker Enfants Malades, Paris, Ile-de-France, France

Frank Bienaime, MD, PhD

• Claude-Taupin, Aurore, Université Paris Cité, INSERM U1151, CNRS UMR-8253, Institut Necker Enfants Malades, Paris, Ile-de-France, France

Aurore Claude-Taupin, PhD

• Kuehn, E. Wolfgang, Albert-Ludwigs-Universitat Freiburg Medizinische Fakultat, Freiburg, BW, Germany

E. Wolfgang Kuehn, MD

• Saunier, Sophie, Université Paris Cité, Institut Imagine, Laboratory of Hereditary Kidney Diseases, INSERM U1163, Paris, Ile-de-France, France

Sophie Saunier, PhD

• Viau, Amandine, Université Paris Cité, Institut Imagine, Laboratory of Hereditary Kidney Diseases, INSERM U1163, Paris, Ile-de-France, France

Amandine Viau, PhD

Background

The Hippo signaling pathway regulates tissue homeostasis through MST1/2–LATS1/2-mediated control of YAP, a transcriptional co-activator of TEAD factors. While YAP signaling is essential during kidney development, its role in adult kidney physiology and disease remains poorly defined. Nephronophthisis (NPH) is a ciliopathy-associated tubulointerstitial kidney disease characterized by progressive inflammation and fibrosis leading to kidney failure. In chronic kidney disease models, YAP is often translocated to the nucleus and both its genetic deletion or pharmacological inhibition has been reported to be protective. In this context, we investigated the impact of YAP loss on kidney physiology and whether its inactivation could attenuate injury in NPH.

Methods

A tubule-specific Yap invalidation mouse model was used to investigate its role in kidney homeostasis. In vitro, kidney tubular cells (mIMCD3, mKEC, MDCK) were subjected to genetic or pharmacological modulation of YAP activity. A non-orthologous mouse model of NPH was used to assess YAP expression and signaling activity, and evaluate the impact of YAP deletion on disease progression.

Results

Tubular Yap deletion resulted in spontaneous kidney injury characterized by tubulointerstitial fibrosis and inflammatory infiltration, highlighting a critical role of tubular YAP in maintaining kidney integrity. These findings were confirmed in vitro, where genetic or pharmacological inhibition of YAP in kidney tubular cells induced pro-inflammatory cytokines expression, whereas YAP activation through inhibition of its upstream kinases LATS1/2 significantly reduced basal inflammatory responses.
In our non-orthologous mouse model of NPH, we observed increased YAP expression and enhanced TEAD-dependent transcriptional activity. In contrast to other chronic kidney disease models, tubular Yap deletion aggravated disease progression, leading to early mortality, marked inflammation with extensive immune cell infiltration, and severe tubulointerstitial fibrosis. In our model of NPH, YAP is required to limit inflammatory injury.

Conclusion

Our findings identify YAP as a regulator of kidney tubular homeostasis, with a strong context-dependent role in kidney disease. In nephronophthisis, YAP is protective by limiting inflammation and fibrosis, highlighting its potential as a therapeutic target in NPH-related ciliopathies.

Acknowledgment

We thank the members of the LEAT, histology, genomics, bioinformatics, cell imaging and image analysis facilities (S.F.R Necker INSERM US24, Paris, France) and of the mouse renal physiology facility (Cordeliers Research Center, Paris, France) for technical assistance. We are grateful to Prof. Eric Olson for sharing Yap^fl/fl mice.

Funding

• Government Support – Non-U.S.