Date: Sunday, June 2, 2019
Session Time: 6:00pm-7:00pm
Presentation Time: 6:00pm-7:00pm
Location: Hall C & D
*Purpose: Chemokine ligand 14 (CCL14), a ligand for CCR1, has been known as a M2 polarizing marker and chemotactic cytokine, which is expressed by fibroblast, monocyte, etc. Although it was first isolated from the hemofiltrate of patients with chronic renal failure, its expression pattern and functional role in chronic kidney disease have never been investigated.
*Methods: To identify potential fibrosis candidate, we performed urine proteomic analysis using three patients’ random urine per each CKD1 and 5. For validating tissue expression of CCL14, one of significantly increased molecule in proteomics analysis, kidney biopsy tissues of IgA nephropathy (three control, nine CKD 3, eight CKD 5) and acute tubular necrosis (ATN) (7 with simple ATN, 7 with combined glomerulonephritis) were stained. Among CKD 3 group, patients with GFR decrease more than 5 ml/min/1.73 m2 within a year were considered to have rapid progression. For in vitro study, we used primary cultured human tubular epithelial cells (hTECs) and glomerular endothelial cells (GECs) to evaluate the functional importance of CCL14 in fibrotic process. Recombinant CCL14 or CCL14 blocking antibody was treated with recombinant TGFβ, and protein expression of fibrotic markers and Annexin V-PI assay was also explored.
*Results: In urine proteomics analysis, we discovered CCL14 showed a 122-fold increase in CKD 5 patients’urine comparing to CKD 1 (p<0.001). In other hands, in human kidney biopsy tissue, CKD 3 patients with rapid progression showed higher expression level of CCL14 (17.33±4.13) compared to non-progressive CKD 3 (10.12±3.60) (p=0.032), control (12.48±2.49) (p=0.019), and CKD 5 (9.63±5.52) (p=0.049). C-reactive protein was adversely lower in progressive CKD 3 patients compared to others (p=0.017), and interstitial inflammation or fibrosis pattern was not different (p=0.861). In acute tubular necrosis, simple ATN showed higher expression level of CCL14 compared to normal control (p=0.022), and lower than combined ATN (p=0.026). In in vitro assay, recombinant CCL14 was a significant inducer of fibrosis in hTEC cells. Moreover, anti-CCL14 antibody treatment showed amelioration of TGFβ-induced fibrosis in hTEC as well as decrease of the proportion of late stage apoptotic cells (Annexin V+/PI+) from 6.2% to 3.8%.
*Conclusions: CCL14 expression tends to increase in patients with kidney injury such as progressive CKD and acute tubular necrosis. Its expression is increased by a rTGFβ-enriched fibrotic environment and it functions as a fibrosis inducer itself. Our results suggest CCL14 could be a promising therapeutic target for kidney fibrosis.
To cite this abstract in AMA style:Lee S, Kim Y, Moon J, Lee H, Han S, Lee J, Cha R, Kim D, Lee C, Kim K, Kim Y, Yang S. Chemokine Ligand 14 is a Novel Therapeutic Target in Kidney Fibrosis [abstract]. Am J Transplant. 2019; 19 (suppl 3). https://atcmeetingabstracts.com/abstract/chemokine-ligand-14-is-a-novel-therapeutic-target-in-kidney-fibrosis/. Accessed March 3, 2021.
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