Reduced Cluster of Differentiation-14 Attenuates Tubulointerstitial Fibrosis in a Murine Unilateral Ureteral Obstruction Model of CKD

Background: Cluster of differentiation-14 (CD14) is a GPI-anchored membrane protein that is predominantly expressed on myeloid cells and serves as a pattern recognition receptor in bacterial infection. We previously demonstrated that CD14 expression was increased in proximal tubular epithelial cells (PTEC) and interstitium in patients and mice with lupus nephritis and chronic kidney disease (CKD). This study investigated the role of CD14 in kidney inflammation and fibrosis in a murine model of unilateral ureteral obstruction (UUO). Methods: UUO or Sham operation (Control group) was performed on 10-week old male wild-type (WT) and CD14 knockout (KO) mice, and sacrificed 3, 7 and 14 days after UUO, and the kidneys were harvested to investigate histopathology and expression of mediators relating to inflammation, fibrosis and tubular injury. The relationship between tubulo-interstitial CD14 expression and kidney function and tubulo-interstitial inflammation and fibrosis in CKD patients was investigated using publicly available transcriptomics datasets from NephroSeq. Results: CD14 expression increased with disease severity and was increased 75.06-fold after 14 days UUO compared to WT Sham mice (p<0.001), and was predominantly localized to proximal tubules undergoing atrophy. Increased CD14 expression was accompanied by immune cell infiltration, and increased expression of vimentin and collagen I. CD14 KO mice with UUO showed reduced immune cell infiltration, tubular atrophy and mediators of cell activation and fibrosis. NephroSeq datasets showed increased tubulo-interstitial cd14 expression in CKD patients compared to healthy subjects (p<0.001) and cd14 expression correlated with serum creatinine level (r = 0.68, p<0.001) and inversely correlated with GFR (r = -0.79, p<0.001). cd14 gene expression also correlated with col1a1 (r = 0.43, p<0.001) and fn1 (r = 0.38, p<0.001) expression, and percentage of interstitial fibrosis and tubular atrophy (r = 0.52, p<0.05). Conclusion: Our findings suggest that CD14 may contribute to tubulo-interstitial fibrosis and deterioration of kidney function in CKD. Funding: Government Support – Non-U.S.