Researchers have identified a key form of collagen that could act as a precision medicine target for chronic kidney disease (CKD). The findings, in Science Translational Medicine, highlight the critical role that collagen V plays in kidney fibrosis among participants in the UK Biobank. The study also demonstrated a pivotal role for collagen V in regulating myofibroblast activation, the degree of renal fibrosis, and renal function in mouse models of kidney injury.
The research team suggests that addressing the expression of collagen type V alpha 1 (COL5A1) and modulating the signaling of a profibrotic integrin could therefore lead to a personalized approach for improving CKD outcomes.
“Our data suggest that, although collagen V is deposited in fibrotic lesions in the diseased kidney, collagen V plays a paradoxical role in the kidney in limiting the degree of fibrosis,” reported Lianjiu Su, PhD, from the University of California, Los Angeles, and co-workers.
They added: “Our data also suggest that the ability to up-regulate Col5a1 after injury exhibits genetic variation, which may be used to design precision medicine approaches.”
CKD affects more than 800 million people globally, with most cases progressing toward kidney fibrosis, where excessive connective tissue builds up in the kidneys. This changes the structure of their extracellular matrix, permanently damaging organ function.
Collagen V is a constituent of the extracellular matrix and is usually deposited where there is kidney fibrosis as well as being linked with histological abnormalities in the kidneys of people with CKD.
To investigate further, the team investigated the role of collagen V in regulating responses to kidney injury and progression to renal failure.
Data from the UK Biobank revealed elevated COL5A1 messenger RNA levels among people with CKD. COL5A was also upregulated in two mouse models of kidney injury.
Deleting Col5a1 in the fibroblasts of mice increased fibrosis and resulted in poorer kidney function after injury, indicating an apparently paradoxical protective role for collagen V in limiting the progression of fibrosis.
Inhibiting the profibrotic integrin αvβ3 with cilengitide rescued the mouse model with the genetic deletion. The drug also benefited kidney function and fibrosis in several strains of mice that could not upregulate Col5a1 in response to injury.
Although cilengitide has been found to be well tolerated in cancer trials, the researchers acknowledge that the study does not address whether it could be administered safely over a prolonged period, which would likely be needed in humans with CKD.
“Notwithstanding, our observations demonstrate that increased deposition of collagen V in fibrotic lesions in the kidney plays a role in preventing an excessive and dysregulated fibrotic response after kidney injury,” they added.
“Upon further investigation, the degree of Col5a1 expression could serve as a marker for precision medicine approaches in identifying individuals who potentially represent a higher risk of progression to CKD or who may benefit from targeted therapies mediating integrin blockade.”
