Stained kidney tissue samples displaying fibrosis below totally different situations: wholesome baseline, kidney damage at 14 days and kidney damage at 28 days. Areas highlighted are within the cortex and medulla. Credit score: Arjun Deb Lab/UCLA
New UCLA analysis performed utilizing mouse fashions and human genetic information has uncovered a important issue that determines how a lot scarring happens following kidney damage, main scientists to determine a possible precision medication strategy to stop persistent kidney illness development.
The examine, revealed in Science Translational Drugs, highlights the function of sort 5 collagen—a minor part of scar tissue—in kidney fibrosis, and reveals how an experimental remedy might assist forestall kidney failure in high-risk people.
Persistent kidney illness is a progressive situation that may outcome from diabetes, hypertension and kidney stones, amongst different causes. It impacts a couple of in seven adults in the USA and 800 million individuals worldwide. Because it advances, extreme fibrosis or buildup of scar tissue impairs the power of the kidneys to filter toxins from the blood and reabsorb water, usually resulting in kidney failure.
There are at present no therapies that immediately goal or reverse this course of, requiring sufferers to bear dialysis or organ transplantation.
“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,” stated Dr. Arjun Deb, the examine’s senior writer and a member of Eli and Edythe Broad Middle of Regenerative Drugs and Stem Cell Analysis at UCLA.
“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.”
How sort 5 collagen determines scarring severity
In a earlier examine specializing in coronary heart damage, Deb recognized that mice missing the power to provide sort 5 collagen suffered extra in depth scarring after a coronary heart assault.
To find out if these identical mechanisms translated to kidney damage, Deb and his crew started analyzing information from the UK Biobank, a long-term examine monitoring greater than 1.5 million individuals. They found that expression of Col5a1, the gene encoding sort 5 collagen, strongly correlated with the chance of creating persistent kidney illness over the course of a decade.
“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,” stated Deb, who’s a professor of drugs (cardiology) and molecular, cell and developmental biology and director of the David Geffen College of Drugs’s cardiovascular theme.
A collection of experiments in mouse fashions confirmed these findings: mice with low Col5a1 developed extra extreme fibrosis and progressed extra quickly to kidney failure following kidney damage. As with people, sort 5 collagen was taking part in a vital function in sustaining the construction and performance of scar tissue. Collagen fibers, Deb defined, are just like the threads that maintain a bit of material collectively.
“Collagens are fibrillar in nature, and they give strength to scar tissue,” he stated. “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.”
With out sort 5 collagen, the physique senses that the scar tissue has fashioned in a weaker, extra disorganized method. This prompts αvβ3 integrins—receptors in fibroblast cells that sense the weakened tissue and reply by producing much more scar tissue. This cycle of extreme fibrosis results in worsening kidney perform and, finally, kidney failure.
Fluorescent imaging of fibrotic kidney scar tissue displaying expression of Col5a1 (purple) and Col1a1 (inexperienced). Credit score: Arjun Deb Lab/UCLA
A precision medication strategy: Blocking integrin αvβ3
Recognizing that extreme integrin exercise was driving fibrosis in animals with decreased sort 5 collagen, the crew sought a solution to block this pathway. They discovered a possible answer in Cilengitide, a drug that disrupts integrin signaling.
Initially developed as an anti-cancer remedy, Cilengitide progressed via scientific trials and was discovered to be protected, however finally not efficient towards most cancers.
The crew discovered that treating animals with decreased sort 5 collagen with Cilengitide considerably diminished kidney fibrosis and slowed illness development. Notably, it had no impact in mice with regular Col5a1 expression, highlighting its potential as a focused remedy for people liable to fast illness development.
“This presents an exciting opportunity to potentially repurpose this drug, which was already deemed safe by the FDA, for a completely different indication,” Deb stated.
Translating findings to scientific software
Deb’s crew is now working to ascertain a blood check to measure Col5a1 ranges in human sufferers with persistent kidney illness to ascertain a scientific threshold for figuring out at-risk people. If validated, this biomarker may very well be used to information remedy selections, pinpointing sufferers who may gain advantage from this focused strategy to slowing illness development.
“Chronic kidney disease 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,” Deb stated. “We can use a simple blood test to measure type 5 collagen levels and identify individuals who could potentially benefit from this drug.”
Past persistent kidney illness, the researchers are additionally investigating whether or not the identical mechanisms contribute to fibrosis within the liver and blood vessels, the place scarring is a significant driver of illness.
Using Cilengitide has not been examined in people as a remedy for extreme scarring and has not been authorized by the Meals and Drug Administration as protected and efficient for this use.
This novel therapeutic strategy is roofed by a patent software filed by the UCLA Know-how Improvement Group on behalf of the Regents of the College of California.
Extra info:
Collagen V regulates renal perform after kidney damage and could be pharmacologically focused to reinforce kidney restore in mice, Science Translational Drugs (2025). www.science.org/doi/10.1126/scitranslmed.ads7714
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