Abstract
It has been found that CD226 plays an important role in regulating
macrophage function, but its expression and function on macrophage
during renal fibrogenesis have not been studied. Our data demonstrated
that CD226 expression in macrophages was obviously upregulated in the
UUO model, while CD226 deficiency attenuated collagen deposition in
renal inerestitum along with fewer number of M1 within renal cortex and
renal medulla and a lower level of proinflammatory factors compared to
control littermates. Further studies demonstrated that Cd226-/–BMDMs
transferring to Cd226+/+ mice could significantly reduce the tubular
injury, collagen deposition and proinflammatory cytokines secretion
compared with WT-BMDMs group and WT-PBS group in adoptively transferring
assay. Mechanistic investigations revealed that CD226 could suppress
KLF4 expression in macrophages, which subsequently promoted more
proinflammatory M1 accumulation in the kidney of WT mice than that of
CD226 deficient mice. In vitro, we silenced KLF4 expression in BMDMs
deriving from WT or CD226 deficient mice and the trend that CD226
promting more numbers of M1 disappeared. Therefore, our results uncover
a pathogenic role of CD226 during the development of CKD by promoting
monocyte infiltration from peripheral blood into the kidney and
enhancing macrophage activation towards to the inflammatory phenotype by
suppressing KLF4 expression.