Epidermal growth factor receptor activation is essential for kidney fibrosis development

Shirong Cao, Yu Pan, Andrew S. Terker, Juan Pablo Arroyo Ornelas, Yinqiu Wang, Jiaqi Tang, Aolei Niu, Sarah Abu Kar, Mengdi Jiang, Wentian Luo, Xinyu Dong, Xiaofeng Fan, Suwan Wang, Matthew H. Wilson, Agnes Fogo, Ming-Zhi Zhang () and Raymond C. Harris ()
Additional contact information
Shirong Cao: Division of Nephrology and Hypertension, Department of Medicine
Yu Pan: Division of Nephrology and Hypertension, Department of Medicine
Andrew S. Terker: Division of Nephrology and Hypertension, Department of Medicine
Juan Pablo Arroyo Ornelas: Division of Nephrology and Hypertension, Department of Medicine
Yinqiu Wang: Division of Nephrology and Hypertension, Department of Medicine
Jiaqi Tang: Division of Nephrology and Hypertension, Department of Medicine
Aolei Niu: Division of Nephrology and Hypertension, Department of Medicine
Sarah Abu Kar: Division of Nephrology and Hypertension, Department of Medicine
Mengdi Jiang: Division of Nephrology and Hypertension, Department of Medicine
Wentian Luo: Division of Nephrology and Hypertension, Department of Medicine
Xinyu Dong: Division of Nephrology and Hypertension, Department of Medicine
Xiaofeng Fan: Division of Nephrology and Hypertension, Department of Medicine
Suwan Wang: Division of Nephrology and Hypertension, Department of Medicine
Matthew H. Wilson: Division of Nephrology and Hypertension, Department of Medicine
Agnes Fogo: Vanderbilt University Medical Center
Ming-Zhi Zhang: Division of Nephrology and Hypertension, Department of Medicine
Raymond C. Harris: Division of Nephrology and Hypertension, Department of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: Abstract Fibrosis is the progressive accumulation of excess extracellular matrix and can cause organ failure. Fibrosis can affect nearly every organ including kidney and there is no specific treatment currently. Although Epidermal Growth Factor Receptor (EGFR) signaling pathway has been implicated in development of kidney fibrosis, underlying mechanisms by which EGFR itself mediates kidney fibrosis have not been elucidated. We find that EGFR expression increases in interstitial myofibroblasts in human and mouse fibrotic kidneys. Selective EGFR deletion in the fibroblast/pericyte population inhibits interstitial fibrosis in response to unilateral ureteral obstruction, ischemia or nephrotoxins. In vivo and in vitro studies and single-nucleus RNA sequencing analysis demonstrate that EGFR activation does not induce myofibroblast transformation but is necessary for the initial pericyte/fibroblast migration and proliferation prior to subsequent myofibroblast transformation by TGF-ß or other profibrotic factors. These findings may also provide insight into development of fibrosis in other organs and in other conditions.

Date: 2023
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DOI: 10.1038/s41467-023-43226-x

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