C-C Motif Chemokine Ligand-17 as a Novel Biomarker and Regulator of Epithelial Mesenchymal Transition in Renal Fibrogenesis

Abstract

CCL17, a chemotactic cytokine produced by macrophages, is known to promote inflammatory and fibrotic effects in multiple organs, but its role in mediating renal fibrosis is unclear. In our study cohort of 234 chronic kidney disease (CKD) patients and 65 healthy controls, human cytokine array analysis revealed elevated CCL17 expression in CKD that correlated negatively with renal function. The area under the receiver operating characteristic curve of CCL17 to predict the development of CKD stages 3b–5 was 0.644 (p < 0.001), with the optimal cut-off value of 415.3 ng/mL. In vitro over-expression of CCL17 in HK2 cells had no effect on cell viability, but increased cell motility and the expression of α-SMA, vimentin and collagen I, as shown by western blot analysis. In a unilateral ureteral obstruction (UUO) mouse model, we observed significantly increased interstitial fibrosis and renal tubule dilatation by Masson’s Trichrome and H&E staining, and markedly increased expression of CCL17, vimentin, collagen I, and α-SMA by IHC stain, qRTPCR, and western blotting. CCL17 induced renal fibrosis by promoting the epithelial-mesenchymal transition, resulting in ECM accumulation. CCL17 may be a useful biomarker for predicting the development of advanced CKD.

Serum chemokine CC‐motif ligand 17 is a predictive marker of severe COVID‐19 in haemodialysis patients: A retrospective observational study

“…In addition, in our data, median with interquartile range of CCL17 values in patients with normal kidney function ( n = 188), patients with chronic kidney disease ( n = 62) and HD patients ( n = 107) were 180 (116–262), 202 (130–288) and 177 (116–284), respectively ( p = .213 by ANOVA). This result is contrary to a previous study that reported CCL17 expression is increased with the progression of chronic kidney disease 9 . Nevertheless, little is known regarding the kinetics of CCL17 during COVID‐19 and further studies are needed to elucidate the reason for the higher cut‐off value of CCL17 for the prediction of severe COVID‐19 in HD patients.…”

“…They also reported that the optimal cut‐off for identifying COVID‐19 requiring oxygen administration is 95 pg/mL 8 . There are no studies with respect to the kinetics of CCL17 in HD patients with COVID‐19, although CCL17 expression is increased with the progression of chronic kidney disease 9 . The kinetics of CCL17 expression in HD patients with COVID‐19 and its ability to predict severity may be different compared with non‐dialysis patients.…”

The predictive markers of severity and mortality in hospitalized hemodialysis patients with COVID‐19 during Omicron epidemic

“…CCL17 is a factor involved in humoral immunity through T‐cell development or homing [12]. In a previous study, CCL17 induced renal fibrosis by promoting the epithelial‐mesenchymal transition with an accumulation of collagen, and the authors additionally demonstrated that serum CCL17 was significantly elevated in patients with CKD and that CCL17 expression levels correlated negatively with renal function [33]. Lebherz‐Eichinger et al investigated serum and urine chemokine levels in patients with CKD and reported that serum CCL17 level was 359 pg/mL (median) in patients with CKD stage 5 [34].…”

CCL17 acts as a novel therapeutic target in pathological cardiac hypertrophy and heart failure

“…CCL17 has also been shown to be involved in Th2-mediated cystic fibrosis ( Tiringer et al, 2013 ), peritoneal fibrosis ( Terri et al, 2021 ), and the granuloma formation of sarcoidosis ( Nguyen et al, 2018 ). Moreover, CCL17 has been confirmed as a circulating biomarker of fibrosis-associated diseases, such as idiopathic pulmonary fibrosis ( Sivakumar et al, 2021 ), cystic fibrosis ( Adib-Conquy et al, 2008 ), peritoneal ( Chen et al, 2020 ), and renal fibrosis ( Hsieh et al, 2021 ; Pai et al, 2020 ). Our present study is the first to link CCL17 directly to age-related and Ang II–induced cardiac fibrosis.…”