Activation of the epidermal growth factor receptor (EGFR) is essential for the development of kidney fibrosis, tissue scarring following injury that can lead to kidney failure.
Now, researchers at Vanderbilt University Medical Center show in a mouse model that deletion of EGFR from myeloid cells, a type of immune cell that arises from the bone marrow, accelerated recovery from acute kidney injury and reduced subsequent fibrosis.
Their findings, reported May 16 in the journal Nature Communications, bring researchers another step closer to finding the first effective treatment for kidney fibrosis, an all-too-common consequence of chronic kidney disease that can lead to kidney failure, the need for dialysis, and death.
“We are among the numerous researchers here at Vanderbilt who have studied EGFR’s mechanisms and roles,” said Raymond Harris, Jr, MD, the Ann and Roscoe R. Robinson Professor of Nephrology, professor of Medicine, and associate director of the Division of Nephrology and Hypertension.
“Our lab has had a long-standing interest in specifically investigating the role of EGFR and its ligands in the regulation of kidney physiology and pathophysiology,” said Harris, who is the paper’s co-corresponding author with Ming-Zhi Zhang, MD, MSc, professor of Medicine.
Epidermal growth factor and its receptor, which stimulate the growth of epidermal tissue, were discovered more than 60 years ago by the late Stanley Cohen, PhD, a Nobel Prize-winning biochemist at VUMC who died in 2020. Today EGFR is the target for a growing number of cancer drugs.
In response to acute kidney injury caused, for example, by ischemia, or inadequate blood flow to the tissues, myeloid cells — notably macrophages and neutrophils — either help the injured tissue recover or they can make the injury worse, setting the stage for fibrosis.
This duality may have something to do with EGFR activation. While EGFR expression is important for recovery following acute injury in the proximal tubules, a key part of the kidney’s filtering unit, abnormally persistent EGFR activation can cause progressive fibrosis.
In the current study, the VUMC researchers found that deleting EGFR from neutrophils promoted apoptosis (cell death), decreasing the severity of post-ischemic kidney injury. In macrophages, EGFR deletion reduced the expression of inflammatory cytokines and increased the expression of anti-inflammatory markers.
In both cases, the result was accelerated recovery from injury and reduced fibrosis.
The coordinated and complementary detrimental effects of persistent EGFR expression in different myeloid cells reinforce the idea that targeting a growth factor receptor discovered two generations ago could be the key to preventing a leading cause of kidney failure.
The paper’s co-first authors are Yu Pan, MD, PhD, Shirong Cao, MD, PhD, and Yinqui Wang PhD.
Co-authors are Jiaqi Tang, PhD, Aolei Niu, PhD, Sarah Abu Kar, MD, Mengdi Jiang, Fenfen Peng, Gabriela Siew, Wentian Luo, MD, PhD, Suwan Wang, Matthew Wilson, MD, PhD, Craig Brooks, PhD, Agnes Fogo, MD, Andrew Terker, MD, PhD, Juan Pablo Arroyo Ornelas, MD, PhD, and Jianchun Chen, MD.
The research was supported by National Institutes of Health grants R01DK051265, R01DK095785, R01DK062794 and P30DK114809, the U.S. Department of Veterans Affairs, the Vanderbilt Center for Kidney Disease, and the Natural Science Foundation of China and Shanghai Pujiang Program.
