A multidisciplinary research team at Vanderbilt University and Vanderbilt Health has identified the protein cadherin-11 as a mediator of kidney injury and potential therapeutic target for chronic kidney disease.
Chronic kidney disease affects nearly 10% of the world’s population and is characterized by inflammation and fibrosis (scarring). It can progress to end-stage kidney failure that requires dialysis or kidney transplantation.
The mechanosensitive protein cadherin-11 (CDH11) has roles in creating cell-cell and cell-substrate junctions and in shaping cellular responses to environmental stimuli. It has been proposed as a biomarker for kidney fibrosis in chronic kidney disease, but its functional role in kidney disease pathogenesis is poorly understood.
W. David Merryman, PhD, Professor of Biomedical Engineering, Medicine, Pediatrics and Pharmacology, and colleagues characterized the role of CDH11 by blocking it genetically or pharmacologically in three different, complementary kidney injury models. They isolated kidney fibroblasts to test CDH11-mediated responses; used cytokine arrays to quantify secretory changes; and used atomic force microscopy to measure tissue stiffness.
The researchers found that CDH11 expression increased after tissue injury. They showed that when CDH11 was genetically missing or pharmacologically blocked, animals had improved survival and kidney function; decreased circulating levels of inflammatory, fibrotic and cardiorenal injury markers; and limited tissue stiffening of the fibrogenic niche.
The findings, reported in the journal Kidney International, establish CDH11 as a major player in kidney fibroblast mechanobiology, tissue stiffening and propagation of kidney injury, the researchers noted. They suggest that targeting CDH11 may be a viable strategy to prevent the progression of chronic kidney disease.
Merryman, the corresponding author, holds the Walters Family Chair. He was joined on the study by 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. The research was supported by the National Institutes of Health (grants R35HL135790, R01HL170546, R01DK108968, F31DK126428, F31HL149168 and K99HL146951), Fondation Leducq, U.S. Department of Veterans Affairs and American Society of Nephrology.
