Cluster of Differentiation-14 Contributes to Tubulointerstitial Inflammation in a Murine Model of CKD

Background: Chronic kidney disease (CKD) is characterized by progressive tubulo-interstitial fibrosis and tubular atrophy leading to irreversible deterioration of kidney function. Low-grade persistent inflammation drives CKD progression, but the underlying mechanism remains obscure. CD14 is a GPI-anchored glycoprotein that is predominantly expressed on myeloid cells. Secretion of pro-inflammatory cytokines by macrophages is CD14-dependent. We previously demonstrated that CD14 expression was increased in proximal tubular epithelial cells (PTEC) and interstitium in kidney biopsies of patients with CKD. This study investigated the role of CD14 in kidney inflammation in a murine model of CKD. Methods: CKD was induced in male wild-type (WT) and CD14 knockout (KO) mice by feeding with casein-based chow containing 0.2% adenine for 8 weeks, after which time kidneys were harvested to assess the expression of mediators of inflammation and kidney injury. Mice fed casein-based chow served as non-CKD controls. The role of CD14 in inflammatory processes was investigated in HK-2 cells that either overexpressed CD14 or were deficient in CD14 expression. Results: CD14 gene expression increased by 17.66 ± 5.64-fold in WT CKD mice compared to non-CKD WT mice, and was predominantly localized to PTEC and the interstitium. Increased CD14 expression was accompanied by proteinuria and increased mediators of inflammation and tubular injury including IL-6, TNF-α, MCP-1, TGF-β1, NGAL and KIM-1. CD14 KO mice with CKD showed significantly reduced expression of pro-inflammatory and pro-fibrotic cytokines and markers of tubular injury, accompanied by reduced proteinuria (p<0.05, for all). HK-2 cells overexpressing CD14 showed increased IL-6, IL-8 and MCP-1 secretion compared to non-transfected cells, and LPS stimulation further augmented cytokine secretion. CD14-deficient HK-2 cells showed significantly reduced IL-6, IL-8 and MCP-1 secretion compared to non-transfected cells. Conclusion: Our data suggest that CD14 contributes to tubulo-interstitial inflammation in murine adenine-induced CKD and may regulate pro-inflammatory cytokine secretion in PTEC. Funding: Government Support – Non-U.S.