Kidney Week

Abstract: TH-PO0054

Endothelin-1/Endothelin Receptor Type B Signaling Negatively Regulates Uromodulin Surface Expression and Secretion

Session Information

• Fluid, Electrolyte, and Acid-Base Disorders: Basic Research
  October 22, 2026 | Location: Exhibit Hall A, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Fluid, Electrolytes, and Acid-Base Disorders

• 1101 Fluid, Electrolyte, and Acid-Base Disorders: Basic

Authors

• Laghmani, Kamel, Centre de Recherche des Cordeliers, Paris, France

Kamel Laghmani, PhD

• Demaretz, Sylvie, Centre de Recherche des Cordeliers, Paris, France

Sylvie Demaretz

• Rampoldi, Luca, Molecular Genetics of Renal Disorders, Division of Genetics and Cell Biology, IRCCS San Raffaele Scientific Institute, Milano, Italy

Luca Rampoldi, PhD

• Devuyst, Olivier, Universitat Zurich, Zürich, ZH, Switzerland

Olivier Devuyst, MD, PhD

• Preisig, Patricia A., Department of Medicine and Cellular and Molecular Physiology, Yale School of Medicine, New Haven, Connecticut, United States

Patricia A. Preisig, PhD

• Alpern, Robert Jay, Department of Medicine and Cellular and Molecular Physiology, Yale School of Medicine, New Haven, Connecticut, United States

Robert Jay Alpern, MD

Background

In the thick ascending limb (TAL), the Na-K-2Cl cotransporter NKCC2 is a key determinant of sodium reabsorption and therefore of blood pressure regulation. Uromodulin (UMOD), exclusively produced by TAL cells, enhances NKCC2 activity, and inappropriately increased UMOD expression has been associated with salt-sensitive hypertension. Conversely, Endothelin-1 (ET-1)/Endothelin receptor type B (ET_B) signaling inhibits NKCC2 and promotes natriuresis, consistent with the observation that ET_B deficiency causes salt-sensitive hypertension. However, potential molecular interactions between ET_B and UMOD remain unknown.

Methods

Protein interactions were assessed by yeast two-hybrid screening of a human kidney cDNA library and co-immunoprecipitation. Colocalization of ET_B and UMOD in mouse kidney was examined by immunohistochemistry. UMOD surface expression was evaluated by biotinylation assays in OKP cells, and UMOD secretion was measured in primary cultured TAL cells.

Results

Yeast two-hybrid screening identified UMOD as a binding partner of the ET_B C-terminus. Co-immunoprecipitation confirmed ET_B–UMOD interaction in OKP cells. Immunohistochemistry demonstrated colocalization of ET_B and UMOD at the apical membrane of TAL cells in mouse kidney. ET_B overexpression significantly reduced UMOD surface expression in OKP cells, and ET-1 treatment further decreased surface UMOD expression in ET_B-overexpressing cells. Consistently, ET-1 treatment for 30 minutes significantly inhibited apical UMOD secretion in primary TAL cells.

Conclusion

Our findings identify UMOD as a novel interacting partner of ET_B in TAL cells and demonstrate that ET-1/ET_B signaling negatively regulates UMOD surface expression and secretion. These observations reveal a previously unrecognized functional link between the ET-1/ET_B and UMOD pathways in the TAL. Since UMOD enhances NKCC2 activity and promotes sodium reabsorption, ET_B-mediated inhibition of UMOD may contribute to the natriuretic and antihypertensive effects of ET-1 signaling. This newly identified regulatory pathway may provide novel insights into the mechanisms underlying salt-sensitive hypertension.

Funding

• Government Support – Non-U.S.