Kidney Week

Abstract: SA-PO0278

Endothelial Hedgehog Interacting Protein Mediates Renal Proximal Tubular Cell Remodeling in a Mouse Model of Ischemia-Reperfusion Injury

Session Information

• AKI: Mechanisms - Cell Signaling
  October 24, 2026 | Location: Exhibit Hall A, 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., Harvard Medical School, 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) initiate/modulate renal inflammatory responses, resulting in renal proximal tubular cell (RPTC) damage during acute kidney injury (AKI), yet the underlying mechanisms remain poorly understood. Hedgehog-interacting protein (Hhip) is highly expressed in ECs, and its aberrant expression has been implicated in pathological EC remodeling. Here, we investigated whether EC–specific Hhip knockout (KO, Hhip^EC-KO) mitigates AKI-RPTCs remodeling in renal ischemia-reperfusion injury (IRI).

Methods

Ten-week-old Hhip^EC-KO mice (C57Bl6 strain) and their respective controls (Hhip^fl/fl) underwent 45 minutes of unilateral IRI or sham surgery along with contralateral nephrectomy and then followed from Day 21 to 56 post-IRI. Mouse endothelial cells (mECs) and RPTCs with or without Hhip (siRNA) ± cisplatin (2µM) exposure were also studied in vitro.

Results

Hhip expression in sham kidneys is largely restricted to glomerular ECs, whereas following IRI, expression is increased in glomerular ECs and robustly induced in RPTCs. Compared to sham controls, IRI-Hhip^fl/fl mice developed severe AKI characterized by high mortality, renal dysfunction, and tubular injury, but greatly protected in IRI-Hhip^EC-KO mice. Of note, the formation of kidney injury molecule-1 (Kim1) (+)-RPTCs, which correlate with tubular injury severity; and vascular cell adhesion molecule 1 (Vcam1) (+)- RPTCs, which are considered failed-repair RPTCs during the transition from AKI to chronic kidney disease transition, were significantly inhibited in the kidney of IRI-Hhip^EC-KO mice. In vitro, mEC-derived Hhip present in conditioned media collected from cisplatin-treated mECs promoted Kim1 and Vcam1 gene expression in naïve RPTCs, whereas these effects were largely prevented when naïve RPTCs were exposed to conditioned media from cisplatin-treated Hhip KO mECs.

Conclusion

Our data suggest that endothelial Hhip deletion provided substantial protection against toxic and ischemic acute tubular injury, mediated, at least in part, through the mitigation of RPTC injury and maladaptive repair pathways following IRI.