Chemokine receptor Cxcr4 contributes to kidney fibrosis via multiple effectors

Abstract

Kidney fibrosis is the final common pathway for virtually every type of chronic kidney disease and is a consequence of a prolonged healing response that follows tissue inflammation. Chronic kidney inflammation ultimately leads to progressive tissue injury and scarring/fibrosis. Several pathways have been implicated in the progression of kidney fibrosis. In the present study, we demonstrate that G protein-coupled chemokine (C-X-C motif) receptor (CXCR)4 was significantly upregulated after renal injury and that sustained activation of Cxcr4 expression augmented the fibrotic response. We demonstrate that after unilateral ureteral obstruction (UUO), both gene and protein expression of Cxcr4 were highly upregulated in tubular cells of the nephron. The increased Cxcr4 expression in tubules correlated with their increased dedifferentiated state, leading to increased mRNA expression of platelet-derived growth factor (PDGF)-α, transforming growth factor (TGF)-β1, and concurrent loss of bone morphogenetic protein 7 (Bmp7). Ablation of tubular Cxcr4 attenuated UUO-mediated fibrotic responses, which correlated with a significant reduction in PDGF-α and TGF-β1 levels and preservation of Bmp7 expression after UUO. Furthermore, Cxcr4(+) immune cells infiltrated the obstructed kidney and further upregulate their Cxcr4 expression. Genetic ablation of Cxcr4 from macrophages was protective against UUO-induced fibrosis. There was also reduced total kidney TGF-β1, which correlated with reduced Smad activation and α-smooth muscle actin levels. We conclude that chronic high Cxcr4 expression in multiple effector cell types can contribute to the pathogenesis of renal fibrosis by altering their biological profile. This study uncovered a novel cross-talk between Cxcr4-TGF-β1 and Bmp7 pathways and may provide novel targets for interrupting the progression of fibrosis.

Resolving the fibrotic niche of human liver cirrhosis using single-cell transcriptomics

“…7d). CXCR4 signaling in both macrophages and endothelia have been associated with promoting tissue fibrosis in mice 44,64 . IL-34, CSF-1 and CX3CL1 interactions with relevant macrophage receptors are known to modulate macrophage function and survival 65,66 ; IL-34 and CSF-1 are potent macrophage mitogens 65 , potentially explaining the increased proliferation observed in SAMs (Extended Data Fig.…”

645. Mucosal-Associated Invariant T cells in Renal Tissue From Patients With Recurrent Urinary Tract Infections

“…Granzyme K, another serum protease, was expressed by a substantial proportion of both the CD8 + and DN MAIT cells but was also similar between the compared study groups (Figures 2A and S6). The expression of chemokine receptors, such as CCR6, CXCR4, and CXCR6, that allow cells to migrate to distinct anatomic compartments such as the urogenital tract, 37–40 did not differ between the study groups either, and these chemokine receptors were expressed by a substantial proportion of the CD8 + and DN MAIT cell populations (Figure 2A). Interleukin‐7 receptor α‐chain (IL‐7Rα), was which is frequently expressed on CD27 + CD28 + CD8 T cells and is lost during differentiation towards a cytotoxic memory profile, 32 also frequently expressed on CD8 + and DN MAIT cells.…”

Ubiquitin Urine Levels in Burn Patients

“…Nevertheless, it could be speculated that differences in the transport capacity of multi-ligand receptors in the proximal tubule, such as megalin or cubilin, may account for the observed differences in ubiquitin excretion (46, 57). Furthermore, chemokine receptor CXCR4 is expressed in the proximale tubule and highly upregulated after renal injury (58, 59). As ubiquitin binding to CXCR4 leads to receptor mediated endocytosis of the receptor-ligand complex (23, 27, 29, 60), changes in the expression level of CXCR4 in the kidney could also contribute to the observed differences in ubiquitin excretion between burn patients with uncomplicated recovery and those who develop sepsis/MOF or die.…”