Kidney Week

Abstract: SA-PO0174

Hedgehog Interacting Protein Mediates the Cross-Talk Between Endothelial Cells and Renal Proximal Tubular Cells in a Mouse Model of Renal Ischemia-Reperfusion Injury

Session Information

• AKI: Mechanisms - 3
  November 08, 2025 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

• 103 AKI: Mechanisms

Authors

• Pang, Yuchao, Centre de Recherche du Centre Hospitalier de l'Universite de Montreal, Montreal, Quebec, Canada

Yuchao Pang, MS, MSc

• Peng, Junzheng, Centre de Recherche du Centre Hospitalier de l'Universite de Montreal, Montreal, Quebec, Canada

Junzheng Peng, MD

• Chang, Shiao-Ying, Centre de Recherche du Centre Hospitalier de l'Universite de Montreal, Montreal, Quebec, Canada

Shiao-Ying Chang, PhD

• Liao, Min-Chun, Centre de Recherche du Centre Hospitalier de l'Universite de Montreal, Montreal, Quebec, Canada

Min-Chun Liao, PhD

• Zhao, Xin-Ping, Centre de Recherche du Centre Hospitalier de l'Universite de Montreal, Montreal, Quebec, Canada

Xin-Ping Zhao

• Rivard, Alain, Centre de Recherche du Centre Hospitalier de l'Universite de Montreal, Montreal, Quebec, Canada

Alain Rivard, MD

• Cote, Jean Maxime, Centre de Recherche du Centre Hospitalier de l'Universite de Montreal, Montreal, Quebec, Canada

Jean Maxime Cote, MD, MS, MSc

• Ingelfinger, Julie R., Massachusetts General Hospital, Boston, Massachusetts, United States

Julie R. Ingelfinger, MD

• Chan, John S.D., Centre de Recherche du Centre Hospitalier de l'Universite de Montreal, Montreal, Quebec, Canada

John S.D. Chan, PhD

• Zhang, Shao-Ling, Centre de Recherche du Centre Hospitalier de l'Universite de Montreal, Montreal, Quebec, Canada

Shao-Ling Zhang, PhD

Background

Endothelial cells (ECs) play a vital role in the responses involved in tubular epithelial cell (TECs) damage that occurs during acute kidney injury (AKI). As abnormal hedgehog interacting protein (Hhip) expression has been linked to endothelial/epithelial-to-mesenchymal transition that appears to promote cellular remodeling in the kidney, we aimed to examine the molecular basis of Hhip-mediated crosstalk between ECs and TECs in renal ischemia-reperfusion injury (IRI).

Methods

The 10-week-old mice with Hhip knock-out (KO) both in ECs (Hhip^EC-KO) and in renal tubules (RT) (Hhip^RT-KO) and their respective controls (Hhip^fl/fl) underwent 45 minutes of unilateral IRI or sham surgery along with contralateral nephrectomy. They then were followed from Day 1 to 7 post-IRI. Mouse endothelial cells (mECs) and renal proximal tubular cells (IRPTCs) with or without Hhip (siRNA) ± cisplatin (2µM) exposure were also studied in vitro.

Results

Compared to sham controls, IRI-Hhip^fl/fl mice developed clear AKI with high mortality rate, renal dysfunction and obvious AKI-related renal tubular cell injury, senescence and apoptosis. In contrast, such changes were significantly ameliorated in the kidneys of IRI-Hhip KO mice, particularly, less AKI-tubular injury in Hhip^EC-KO than Hhip^RT-KO mice. In vitro, naïve IRPTCs exposed to conditioned media harvested from mECs treated with cisplatin exhibited greater cellular senescence with nuclear enlargement with both mono- or multi-nuclei and increased cytoskeleton destabilization. Those changes were largely prevented in naïve IRPTCs exposed to the conditioned media harvested from Hhip KO mECs treated with cisplatin.

Conclusion

Our data suggest that Hhip KO in ECs prevented or ameliorated AKI-induced renal tubular injury. This potential protection may be mediated, at least in part, by the inhibition of Hhip-mediated tubular cell senescence.

Funding

• Other NIH Support

Digital Object Identifier (DOI)

• doi: 10.1681/ASN.2025w3z0aab5