Selective Targeting of Vascular Endothelial YAP Activity Blocks EndMT and Ameliorates Unilateral Ureteral Obstruction-Induced Kidney Fibrosis

Yafeng Ren; Yuwei Zhang; Lu Wang; Fuqian He; Mengli Yan; Xiaoheng Liu; Yangying Ou; Qinkai Wu; Tao Bi; Shiyuan Wang; Jian Liu; Bi-Sen Ding; Li Wang; Jie Qing

doi:10.1021/acsptsci.1c00010

Selective Targeting of Vascular Endothelial YAP Activity Blocks EndMT and Ameliorates Unilateral Ureteral Obstruction-Induced Kidney Fibrosis

ACS Pharmacol Transl Sci. 2021 Apr 5;4(3):1066-1074. doi: 10.1021/acsptsci.1c00010. eCollection 2021 Jun 11.

Authors

Yafeng Ren¹, Yuwei Zhang^{2

3}, Lu Wang^{2

3}, Fuqian He⁴, Mengli Yan¹, Xiaoheng Liu^{2

3}, Yangying Ou^{2

3}, Qinkai Wu⁵, Tao Bi^{2

3}, Shiyuan Wang^{2

3}, Jian Liu^{2

3}, Bi-Sen Ding^{1

6

7}, Li Wang³, Jie Qing^{2

3

1}

Affiliations

¹ Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu 610064, China.
² National Traditional Chinese Medicine Clinical Research Base, Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou 646000, China.
³ Research Center of Integrated Traditional Chinese and Western Medicine, Affiliated Traditional Medicine Hospital, Southwest Medical University, Luzhou 646000, China.
⁴ The Center of Gerontology and Geriatrics and National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu 610041, China.
⁵ Michael Smith Laboratories, University of British Columbia, Vancouver V6T1Z4, Canada.
⁶ Fibrosis Research Center, Icahn School of Medicine at Mount Sinai, New York, New York 10128, United States.
⁷ Ansary Stem Cell Institute, Weill Cornell Medicine, New York, New York 10065, United States.

Abstract

Kidney fibrosis is accompanied by vascular dysfunction. Discovering new ways to ameliorate dysfunctional angiogenesis may bypass kidney fibrosis. YAP (Yes-associated protein) plays a multifaceted role during angiogenesis. Here, we found that selectively targeting YAP signaling in the endothelium ameliorates unilateral ureteral obstruction (UUO)-induced kidney fibrosis. Genetic deletion of Yap1, encoding YAP protein, in VE-cadherin⁺ endothelial cells inhibited endothelial-to-mesenchymal transition (EndMT) and dysfunctional angiogenesis and improved obstructive nephropathy and kidney fibrosis. Treatment with the systemic YAP inhibitor verteporfin worsened kidney fibrosis symptoms because of its lack of cell specificity. In an attempt to identify endothelial-specific YAP modulators, we found that G-protein-coupled receptor coagulation factor II receptor-like 1 (F2RL1) was highly expressed in vessels after UUO-induced kidney fibrosis. The F2RL1 peptide antagonist FSLLRY-NH2 selectively blocked YAP activity in endothelial cells and ameliorated kidney fibrosis. Thus, selective antagonization of endothelial YAP activity might bypass kidney fibrosis and provide new avenues for the design of antifibrotic therapies.