Collagen V regulates renal function after kidney injury and can be pharmacologically targeted to enhance kidney repair in mice

Kidney fibrosis determines clinical outcomes in individuals with chronic kidney disease (CKD). The stoichiometric ratio of collagens in renal scar differs from that of healthy kidney extracellular matrix (ECM), but the functional importance of altered collagen types in injured kidneys remains unclear. Using human population studies, we show that circulating protein and renal mRNA amounts of collagen V A1 (COL5A1) exhibited associations with kidney disease and incident CKD risk. We show that <i>Col5a1</i> regulates the degree of postinjury fibrosis and renal function. Mice with conditionally knocked out <i>Col5a1</i> (<i>Col5a1</i> CKO) exhibited decreased renal function and greater renal fibrosis after dietary adenine- or ureteric obstruction-mediated kidney injury. Renal fibroblasts in <i>Col5a1</i> CKO animals up-regulated the profibrotic αvβ3 integrin. Inhibition of αvβ3 signaling with a small molecule, cilengitide, rescued postinjury renal function in <i>Col5a1</i> CKO animals. Using the hybrid mouse diversity panel that comprises 100 diverse inbred strains of mice, we observed that gene expression of <i>Col5a1</i> after injury exhibited genetic variation across 100 strains. Strains with low <i>Col5a1</i> expression after injury exhibited worse renal function compared with animals that had higher degrees of expression. We next measured <i>Col5a1</i> expression in peripheral blood mononuclear cells in mice to identify nonresponder strains that did not have increased <i>Col5a1</i> expression after kidney injury. We observed that administration of cilengitide in nonresponder strains significantly rescued postinjury renal fibrosis and function. These studies point to the feasibility of precision medicine approaches to target <i>Col5a1</i> for enhancing renal repair.