VUMC study raises hope for improving treatment of kidney diseaseFeb. 2, 2022, 2:32 PM
by Bill Snyder
Researchers at Vanderbilt University Medical Center have revealed an important mechanism in the kidney by which a cell surface receptor known as DDR1 fans the flames of inflammation and fibrosis that ultimately lead to kidney failure.
Their findings, published recently in JCI Insight, a journal of the American Society for Clinical Investigation, provide further evidence that developing a drug to block DDR1 activity potentially could be beneficial for the treatment of kidney disease.
Fibrosis, a consequence of chronic kidney injury, is the excessive and damaging deposition of extracellular matrix components, notably collagen, along the tubules that filter waste products from the blood.
“In general, fibrosis is irreversible,” said Ambra Pozzi, PhD, professor of Medicine at VUMC and current president of the American Society for Matrix Biology. “Once you get it, your kidneys stop working and you need a replacement, such as dialysis or kidney transplant.”
An estimated 37 million Americans have chronic kidney disease, and nearly 800,000 are on dialysis or awaiting kidney transplant due to end-stage kidney disease. Medicare spending on chronic and end-stage kidney disease exceeded $119 million in 2018, according to government figures.
“It’s a huge problem,” added Corina Borza, PhD, research assistant professor of Medicine at VUMC and the paper’s co-corresponding author with Pozzi. “That’s why it’s very important to block this process before kidney function is lost.”
In their study, Pozzi, Borza and their colleagues found that mice lacking the DDR1 gene had reduced renal inflammation and fibrosis in a model of acute kidney injury that progresses to chronic kidney disease, compared to mice that expressed the receptor.
Lack of DDR1 also was associated with decreased phosphorylation of BCR and STAT3, proteins involved in pro-inflammatory and pro-fibrotic signaling.
In the kidney, DDR1 expression increases following acute or chronic injury. “That’s why targeting this receptor is very attractive,” Borza explained. “It’s not there in the healthy cells that are the target of the injury, namely renal proximal tubule epithelial cells. You can inhibit it in injured cells and have a positive outcome.”
DDR1 also is involved in fibrotic diseases of the liver and lung. “We are studying the kidney,” Pozzi said, “but we hope our finding will open the door to studying this receptor in other fibrotic diseases.”
Other VUMC researchers contributing to the study included Gema Bolas, PhD, Fabian Bock, MD, PhD, Xiuqi Zhang, PhD, Favour Akabogu, Ming-Zhi Zhang, MD, Mark de Caestecker, MD, PhD, Min Yang, MD, Hai-chun Yang, MD, PhD, Ethan Lee, MD, PhD, Agnes Fogo, MD, Hayes McDonald, PhD, and Roy Zent, MD, PhD.
The research was supported in part by the U.S. Department of Veterans Affairs and by National Institutes of Health grants DK114809, DK119212 and DK069921.