Cluster of Differentiation-14 Contributes to Tubulo-Interstitial Fibrosis in a Murine Model of CKD
- CKD: Pathobiology - I
November 04, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2203 CKD (Non-Dialysis): Mechanisms
- Chan, Tak Mao Daniel, Department of Medicine, School of Clinical Medicine, the University of Hong Kong, Hong Kong SAR, Hong Kong
- Oh, In Young, Department of Medicine, School of Clinical Medicine, the University of Hong Kong, Hong Kong SAR, Hong Kong
- Yu, Jing, Department of Medicine, School of Clinical Medicine, the University of Hong Kong, Hong Kong SAR, Hong Kong
- Yung, Susan, Department of Medicine, School of Clinical Medicine, the University of Hong Kong, Hong Kong SAR, Hong Kong
Chronic kidney disease (CKD) is characterized by progressive tubulo-interstitial fibrosis and tubular atrophy, leading to kidney failure. CD14 is a GPI-anchored membrane protein that functions as a pattern recognition receptor in sepsis. We previously demonstrated that tubulo-interstitial CD14 expression was increased in kidney biopsies showing CKD from patients without sepsis. We further investigated the role of CD14 in the pathogenesis of tubulo-interstitial inflammation and fibrosis in CKD.
CKD was induced in wild-type (WT) and CD14-knockout (KO) mice by feeding with casein-based chow containing 0.2% adenine for 8 weeks. Mice were sacrificed, kidneys were harvested and histopathological changes examined. Mice fed casein-based chow served as non-CKD controls. The role of CD14 in inflammatory and fibrotic processes was investigated in HK-2 cells that overexpressed CD14.
Tubulo-interstitial CD14 expression was increased in WT CKD mice compared with non-CKD WT controls. WT CKD mice showed tubular atrophy, influx of F4/80+CD260+ macrophages and increased tubulo-interstitial α-smooth muscle actin, fibronectin and collagen expression. CD14-KO mice with CKD showed less severe histopathological abnormalities and reduced immune cell infiltration, with decreased expression of mediators of fibrosis. HK-2 cells overexpressing CD14 showed increased fibronectin expression and IL-6, IL-8 and MCP-1 secretion compared to non-transfected cells, mediated in part through increased p38 MAPK and PI3K phosphorylation, and TGF-β1 stimulation further augmented fibronectin expression and cytokine secretion.
Our data suggest that CD14 contributes to tubulo-interstitial inflammation and fibrosis in murine adenine-induced CKD.
- Government Support – Non-U.S.