Type 5 Collagen Linked to Kidney Scarring, Offers New Treatment Hope for Patients With CKD

Investigators of a study published in Science Translational Medicine discovered a critical factor that determines how much scarring will occur following kidney injury in patients with chronic kidney disease (CKD). In their research, they found the role of type 5 collagen—which is a minor component of scar tissue—in kidney fibrosis and showed how an experimental therapy may prevent the onset of kidney failure in patients who are considered high risk.^1,2

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CKD is a progressive condition that often results from diabetes, high blood pressure, and kidney stones, as well as other factors. It affects over 1 in 7 US adults and about 800 million people worldwide. As the disease advances, the excessive fibrosis, or buildup of scar tissue, impacts the kidneys’ ability to properly filter toxins from the blood and reabsorb water, which often leads to kidney failure. Currently, there are no therapies that directly target or reverse this process, according to the investigators, resulting in many patients having to undergo dialysis or organ transplantation.²

“Fibrosis, or scarring, is one of the strongest predictors of kidney failure, but it has not been clear why some people develop more extensive kidney scarring than others,” senior study author Arjun Deb, MD, member of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research and professor of medicine at University of California Los Angeles Health Sciences (UCLA), said in a news release.²

In a prior study, the investigators determined that in mouse models with heart injury, models that lacked the ability to produce type 5 collagen suffered more extensive scarring following a heart attack. Additionally, they knew that the stoichiometric ratio of collagens in renal scar differs from that of healthy kidney extracellular matrix, but its functional importance within injured kidneys was not clear. Using these data as a reference point, the investigators conducted a new study to assess whether these mechanisms also translated to kidney injury in patients with CKD. They analyzed data from human population studies from UK Biobank, which is a long-term study tracking over 1.5 million people.^1,2

The authors observed that a circulating protein and renal mRNA amounts of collagen 5A1 (Col5a1) were associated with kidney disease and incident CKD risk. Additionally, they found that the protein regulated the degree of postinjury fibrosis and renal function.¹

They further assessed this in mouse models. Mice that had conditionally knocked out Col5a1 (Col5a1 CKO) had decreased renal function and greater renal fibrosis following dietary adenine or ureteric obstruction-mediated kidney injury. Additionally, renal fibroblasts in Col5a1 CKO mice upregulated the profibrotic αvβ3 integrin, and inhibition of αvβ3 signaling with cilengitide rescued postinjury renal function in the Col5a1 CKO mice.

“Collagens are fibrillar in nature, and they give strength to scar tissue. The way the fibers are arranged is very important. Type 5 collagen ensures the fabric of a scar is not woven haphazardly—that it is instead structured and stable,” said Deb in the news release. “Our findings indicate that differences in type 5 collagen expression help explain this variation and that testing for expression of this gene or protein could identify people at greater risk. This gave us a clue that, in humans, Col5a1 expression could potentially be used as a biomarker to identify individuals who would be more likely to progress to kidney failure.”²

Further, using the hybrid mouse diversity panel that comprised 100 diverse inbred strains of mice, the investigators also observed that gene expression of Col5a1 following injury displayed genetic variation across 100 different strains. Specifically, strains that had low Col5a1 expression following injury exhibited worse renal function compared with animals that had higher degrees of expression, wrote the articles. Col5a1 expression in peripheral blood mononuclear cells in mice was also measured to identify nonresponder strains that did not have increased Col5a1 expression after kidney injury. The administration of cilengitide in nonresponder strains was found to significantly rescue postinjury renal fibrosis and function. With these findings, the investigators noted that there is feasibility of precision medicine approaches to target Col5a1 to enhance renal repair, therefore improving outcomes for patients with CKD and slowing their disease progression.¹

“This presents an exciting opportunity to potentially repurpose this drug, which was already deemed safe by the FDA, for a completely different indication. CKD presents a large time window of opportunity for intervention, and you need a precision medicine approach to determine who is likely to have accelerated disease progression and require renal replacement therapies,” explained Deb. “We can use a simple blood test to measure type 5 collagen levels and identify individuals who could potentially benefit from this drug.”²

REFERENCES

1. Su L, Sun Q, Li Y, et al. Collagen V regulates renal function after kidney injury and can be pharmacologically targeted to enhance kidney repair in mice. Sci. Transl. Med. 2025;17(793): eads7714. doi:10.1126/scitranslmed.ads7714

2. University of California — Los Angeles Health Sciences. UCLA researchers identify precision medicine approach for preventing kidney failure. News release. April 9, 2025. Accessed April 22, 2025. https://www.eurekalert.org/news-releases/1079534