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FGF23 ameliorates ischemia-reperfusion induced acute kidney injury via modulation of endothelial progenitor cells: targeting SDF-1/CXCR4 signaling

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Huang Ming Chang, Kang Yung Peng, Chieh Kai Chan, Chiao Yin Sun, Ying Ying Chen, Han Mei Chang, Chun Lin Huang, Pei Chun Liu, Peng Ying Chen, Kuo Chuan Wang, Wei Jie Wang, Chen Chi Wu, Yu Feng Lin, Tai Shuan Lai, Tao Min Huang, Guang Huar Young, Shuei Liong Lin, Marlies Ostermann, Tzong Shinn Chu, Jeff S. Chueh & 1 more Vin Cent Wu

Original languageEnglish
Article number409
JournalCell Death and Disease
Issue number5
PublishedMay 2021

Bibliographical note

Funding Information: This study was supported by grants from the Ministry of Science and Technology, Taiwan, R.O.C. (MOST 106-2321-B-182-002, MOST 106-2314-B-002-166-MY3, MOST 107-2314-B-002-026-MY3), National Taiwan University Hospital-Taipei Veterans General Hospital Joint Research Program (#NTUH-TVGH VN103-01, #NTUH-TVGH VN104-07, #NTUH-TVGH VN105-04) and National Taiwan University Hospital (105-S3061, 107-S3809, UN103-082, UN106-014, 105-P05, 106-P02, 107-T02). Publisher Copyright: © 2021, The Author(s). Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

King's Authors


The levels of fibroblast growth factor 23 (FGF23) rapidly increases after acute kidney injury (AKI). However, the role of FGF23 in AKI is still unclear. Here, we observe that pretreatment with FGF23 protein into ischemia-reperfusion induced AKI mice ameliorates kidney injury by promoting renal tubular regeneration, proliferation, vascular repair, and attenuating tubular damage. In vitro assays demonstrate that SDF-1 induces upregulation of its receptor CXCR4 in endothelial progenitor cells (EPCs) via a non-canonical NF-κB signaling pathway. FGF23 crosstalks with the SDF-1/CXCR4 signaling and abrogates SDF-1-induced EPC senescence and migration, but not angiogenesis, in a Klotho-independent manner. The downregulated pro-angiogenic IL-6, IL-8, and VEGF-A expressions after SDF-1 infusion are rescued after adding FGF23. Diminished therapeutic ability of SDF-1-treated EPCs is counteracted by FGF23 in a SCID mouse in vivo AKI model. Together, these data highlight a revolutionary and important role that FGF23 plays in the nephroprotection of IR-AKI.

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