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

Kidney fibrosis an important determinant of clinical outcomes in individuals with chronic kidney disease (CKD). The stoichiometric ratio of collagens in renal scar tissue differs from that of ECM of healthy kidneys but the functional importance of altered collagen types injured kidneys remains unclear. Using population studies and multiple independent clinical datasets, we show that circulating protein and renal mRNA amounts of Col5a1 exhibited associations with kidney disease and incident CKD risk. Using murine models of tubulo-interstitial kidney injury, we show that Col V regulates the degree of post injury fibrosis and renal function. We demonstrated that mice with conditionally knocked out Col5a1 (Col5a1CKO ) exhibited decreased renal function and greater renal fibrosis after kidney injury . Renal fibroblasts in Col5a1CKO animals upregulated 𝛼vβ3 integrin. Inhibition of 𝛼vβ3 signaling with a small molecule, cilengitide, rescued post-injury renal function in Col5a1 CKO animals. Using the hybrid mouse diversity panel (HMDP) that comprises 100 diverse inbred strains of mice, we observed that the ratio of expression of Col5a1 after injury compared to healthy animals exhibited genetic variation . Strains with low Col5a1 ratios exhibited worse renal function compared to animals that had higher ratios . Col5a1 expression in peripheral blood mononuclear cells after injury compared to uninjured animals to identify Col5a1-non responder strains, we demonstrate that cilengitide can significan tly rescue kidney function in non-responder strains . Overall we found that Col V regulates renal function and fibrosis after kidney injury. These data suggest the feasibility of precision medicine approaches for targeting pathways downstream of Col5a1 to promote kidney repair. Generation of Col5a1CKO Mice:Col1a2CreERT mice were crossed with Col5a1 floxed mice. Tamoxifen was administered to Cre(-) or Cre+Col5a1fl/fl animals with 7days (0.5mg/kg) from starting model. To induce kidney fibrosis, Cre(-) (Col1a2 cre(-) Col5a1 fl/fl) and Col5a1 CKO (Col1a2 cre(+) Col5a1 fl/fl) mice were fed a 0.2% adenine diet for 28 days. For experiments involving cilengitide, 20 mg/kg of cilengitide, diluted in PBS, was administered via IP injection every other day.