FKN Facilitates HK-2 Cell EMT and Tubulointerstitial Lesions via the Wnt/β-Catenin Pathway in a Murine Model of Lupus Nephritis

Abstract

Fractalkine (FKN), also known as chemokine (C-X3-C motif) ligand 1, constitutes an intriguing chemokine with a documented role in the development of numerous inflammatory diseases including autoimmune disease. Specifically, it has been reported that FKN is involved in the disease progression of lupus nephritis (LN). The epithelial-mesenchymal transition (EMT) plays a significant role in the formation of tubulointerstitial lesions (TIL), which are increasingly recognized as a hallmark of tissue fibrogenesis after injury. However, the correlation between FKN and EMT or TIL in LN has not been determined. To investigate the potential role of FKN in EMT and TIL, MRL lymphoproliferation (MRL/lpr) strain mice were treated with an anti-FKN antibody, recombinant-FKN chemokine domain, or isotype antibody. Our results revealed that treatment with the anti-FKN antibody improved EMT, TIL, and renal function in MRL/lpr mice, along with inhibiting activation of the Wnt/β-catenin signaling pathway. In contrast, administration of the recombinant-FKN chemokine domain had the opposite effect. Furthermore, to further explore the roles of FKN in EMT, we assessed the levels of EMT markers in FKN-depleted or overexpressing human proximal tubule epithelial HK-2 cells. Our results provide the first evidence that the E-cadherin level was upregulated, whereas α-SMA and vimentin expression was downregulated in FKN-depleted HK-2 cells. In contrast, overexpression of FKN in HK-2 cells enhanced EMT. In addition, inhibition of the Wnt/β-catenin pathway by XAV939 negated the effect of FKN overexpression, whereas activation of the Wnt/β-catenin pathway by Ang II impaired the effect of the FKN knockout on EMT in HK-2 cells. Together, our data indicate that FKN plays essential roles in the EMT progression and development of TIL in MRL/lpr mice, most likely through activation of the Wnt/β-catenin signaling pathway.

Review on Inflammation Markers in Chronic Kidney Disease

“…CX3CL1, also known as fractalkine, has been involved in several kidney diseases, however, studies show conflicting results regarding its disease-promoting or protecting effect [ 133 ]. Nonetheless, recent mice studies show that it could play an essential role in lupus nephritis with the development of tubulointerstitial lesions through activation of the Wnt/β-catenin signaling pathway [ 134 ]. Additionally, in vitro studies further evaluated the CX3CL1 and Wnt/β-catenin signaling pathway to find that it is associated with podocyte damage and could account for progressive AKI [ 135 ].…”

Depletion of Fractalkine Ameliorates Renal Injury and Treg Cell Apoptosis Via the p38MAPK Pathway in Lupus-prone Mice

“…In the pathogenesis of acute respiratory distress syndrome, a high Fractalkine expression promoted the phosphorylation of p38MAPK and induced the apoptosis of A549 cells [47]. A previous study determined that autoimmune renal injury and Ig production in MRL-Fas/lpr mice were dependent on p38 MAPK activation [48]. In SLE, the speci c p38MAPK inhibitor SB203580 blocked T cell apoptosis induced by the anti-CD3 monoclonal antibody [49].…”

Tanshinone IIA attenuates high glucose-induced epithelial-to-mesenchymal transition in HK-2 cells through VDR/Wnt/β-catenin signaling pathway

“…The Wnt pathway has been reported to play an important role in renal tubular EMT and renal fibrosis. In the study of Fu et al [31], the Wnt pathway was activated in the progression of EMT and tubulointerstitial lesions. Besides, kallistatin was proved to ameliorate EMT and renal fibrosis by inhibiting the Wnt pathway [32].…”