Block this Receptor to Derail Kidney Fibrosis

Block this Receptor to Derail Kidney Fibrosis
New study details pathways promoting kidney inflammation and fibrosis, raising new concepts for treatment.

The mechanism by which discoidin domain receptor 1 (Ddr1), a cell surface receptor activated by collagen, promotes inflammation and fibrosis has been outlined in a new study from investigators at Vanderbilt University Medical Center.

Published in JCI Insight, the findings provide further evidence that developing a drug to block DDR1 activity could be beneficial for the treatment of kidney disease.

“Our study identifies the collagen receptor DDR1 as a major mediator of inflammation and excessive deposition of collagen, two major drivers of kidney disease and ultimately fibrosis,” said Pozzi. “Because fibrosis leads to loss of organ function, we believe that preventing DDR1 function might reduce both pro-inflammatory and pro-fibrotic responses.”

The Need to Halt Fibrosis

Fibrosis, the final feature of chronic kidney injury, is the excessive and damaging deposition of extracellular matrix components, notably collagen, within the glomeruli and along the tubules.

“We hope our finding will open the door to studying this receptor in other fibrotic diseases.”

The condition is generally irreversible, Pozzi explains, eventually hindering kidney function and causing patients to seek dialysis or kidney transplant.

In the United States, it’s estimated that 37 million people – or 15 percent of all adults – have chronic kidney disease, and the CDC reports that nearly 800,000 Americans are on dialysis or awaiting transplant due to end-stage kidney disease.

“It’s a huge problem,” added Corina Borza, Ph.D., a research assistant professor of medicine at Vanderbilt and the paper’s co-corresponding author with Pozzi. “That’s why it’s very important to block this process before kidney function is damaged and lost.”

DDR1 as a Therapeutic Target

In their study, Pozzi, Borza and colleagues compared mice lacking the Ddr1 gene to mice that expressed the receptor, finding in those lacking the gene to have reduced renal inflammation and fibrosis in a model of acute kidney injury that progresses to chronic kidney disease.

“Our study identifies the collagen receptor DDR1 as a major mediator of inflammation and excessive deposition of collagen, two major drivers of kidney disease and ultimately fibrosis. We believe that preventing DDR1 function might reduce both pro-inflammatory and pro-fibrotic responses.”

Lack of Ddr1 was also associated with decreased phosphorylation of breakpoint cluster region (BCR) protein and signal transducer and activator of transcription 3 (STAT3), two proteins involved in pro-inflammatory and pro-fibrotic signaling, respectively.

In the kidney, Ddr1 expression increases following acute and chronic injury.

“It’s not expressed in healthy kidneys,” Pozzi said. “However, following injury its expression increases in injured cells, particularly tubular cells. Thus, its inhibition in injured cells might have a positive outcome.”

“That’s why targeting this receptor is very attractive,” Borza added.

While the current study is focused on the role of Ddr1 in kidney fibrosis, Pozzi notes that Ddr1 is also involved in fibrotic diseases of the liver and lung.

“We hope our finding will open the door to studying this receptor in other fibrotic diseases,” she said.