A multidisciplinary research team at Vanderbilt University has identified a protein called cadherin-11 as a major driver of kidney injury and scarring, opening a potential new pathway to slow or prevent chronic kidney disease (CKD) progression. The findings, published in the journal Kidney International, suggest that targeting this protein could help the nearly 10% of the world's population affected by CKD, a condition characterized by inflammation and fibrosis that can eventually lead to kidney failure requiring dialysis or transplantation.

What Is Cadherin-11 and Why Does It Matter?

Cadherin-11 (CDH11) is a mechanosensitive protein that helps create connections between cells and influences how cells respond to their environment. While researchers had suspected it played a role in kidney fibrosis, its actual function in kidney disease was poorly understood until now. The Vanderbilt team, led by W. David Merryman, PhD, Professor of Biomedical Engineering, Medicine, Pediatrics and Pharmacology, set out to test whether blocking this protein could slow kidney damage.

The researchers used three different kidney injury models to study cadherin-11's role. They isolated kidney fibroblasts (cells that produce scar tissue), measured inflammatory markers in the blood, and used atomic force microscopy to assess tissue stiffness. What they discovered was striking: when cadherin-11 was either genetically removed or pharmacologically blocked, the results were dramatic.

How Did Blocking This Protein Help?

In animal models, blocking cadherin-11 led to measurable improvements across multiple markers of kidney health. Animals that had the protein blocked showed improved survival rates and better kidney function compared to controls. They also had lower levels of inflammatory and fibrotic markers circulating in their blood, suggesting the body's damaging immune response was being dampened. Perhaps most importantly, tissue stiffening,a hallmark of kidney scarring,was limited when cadherin-11 was blocked.

"The findings establish cadherin-11 as a major player in kidney fibroblast mechanobiology, tissue stiffening and propagation of kidney injury," the researchers noted in their published work.

W. David Merryman, PhD, Professor of Biomedical Engineering, Medicine, Pediatrics and Pharmacology at Vanderbilt University

These results suggest that cadherin-11 isn't just a bystander in kidney disease; it's actively driving the scarring process. By understanding this mechanism, researchers can now design drugs that specifically target this protein to slow disease progression.

Steps to Understanding Your Kidney Health Risk

• Know Your Risk Factors: Chronic kidney disease commonly develops from diabetes, high blood pressure, glomerulonephritis (inflammation of the kidney's filtering units), and genetic disorders. If you have any of these conditions, regular kidney function monitoring is essential.
• Get Regular Screening: A simple blood test measuring creatinine levels and a urine test for protein can detect early kidney disease. Early detection allows for interventions that may slow progression.
• Understand Disease Progression: CKD develops gradually, with inflammation and scarring accumulating over time. Treatments that target the underlying mechanisms, like blocking cadherin-11, could potentially halt this progression before kidney failure occurs.

What Does This Mean for Kidney Disease Patients?

Currently, chronic kidney disease affects nearly 10% of the global population, and many patients eventually progress to end-stage kidney failure, requiring dialysis or transplantation. The standard treatments available today,such as blood pressure control and diabetes management,help slow progression but don't address the underlying scarring process.

If cadherin-11 blocking drugs can be successfully developed and tested in humans, they could offer a fundamentally new approach: directly targeting the mechanism that causes kidney tissue to stiffen and scar. This could potentially delay or prevent the need for dialysis by years or even decades, dramatically improving quality of life for millions of patients.

The research was supported by the National Institutes of Health, the Fondation Leducq, the U.S. Department of Veterans Affairs, and the American Society of Nephrology. The team included Tessa Huffstater, PhD; J. Caleb Snider, PhD; Natalie Noll, PhD; David Armstrong, MD, PhD; Matthew Bersi, PhD; Agnes Fogo, MD; Leslie Gewin, MD; and Roy Zent, MBBCh, PhD.

What Happens Next in the Research Pipeline?

While these findings are promising, the research is still in the preclinical stage. The next step is to develop pharmaceutical compounds that can safely and effectively block cadherin-11 in human patients, followed by clinical trials to confirm the benefits seen in animal models. Given the massive burden of kidney disease worldwide and the lack of disease-modifying treatments currently available, this research represents a significant step forward in nephrology.

The discovery also highlights the importance of basic research in understanding disease mechanisms. By identifying cadherin-11's role in kidney fibrosis, scientists have created a new therapeutic target that pharmaceutical companies can now pursue, potentially leading to treatments that could transform outcomes for millions of CKD patients globally.