Targeting CC chemokine ligand (CCL) 20 by miR-143-5p alleviate lead poisoning-induced renal fibrosis by regulating interstitial fibroblasts excessive proliferation and dysfunction

Abstract

Environmental lead contamination can cause chronic renal disease with a common clinical manifestation of renal fibrosis and constitutes a major global public health threat. Aberrant proliferation and extracellular matrix (ECM) accumulation in renal interstitial fibroblasts are key pathological causes of renal fibrosis. However, the mechanism underlying lead-induced kidney fibrosis remains unclear. The present study analyzed gene expression prolifes in lead acetate-treated primary mice renal interstitial fibroblasts and confirmed the aberrant expression of CC chemokine ligand (CCL) 20, one of the most obvious up-regulated genes. Analogously, lead acetate exposure dose-dependently increased CCL20 transcription, protein expression and release. Knockdown of CCL20 suppressed lead acetate-induced fibroblast proliferation, hydroxyproline contents, transforming growth factor-beta production and ECM-related protein (Collagen I and fibronectin) expression. Bioinformatics analysis predicted five top miRNAs targeting CCL20. Among them, miR-143-5p expression was dose-dependently decreased in lead acetate-treated fibroblasts. Mechanistically, miR-143-5p directly targeted CCL20. Elevation of miR-143-5p antagonized lead acetate-induced fibroblast proliferation, hydroxyproline and ECM-related protein expression, which were reversed by CCL20 overexpression. Additionally, CCL20 knockdown suppressed lead acetate-mediated Smad2/3 and AKT pathway activation. Notably, miR-143-5p overexpression attenuated the activation of the Smad2/3 and AKT pathway in lead acetate-exposed fibroblasts, which was counteracted by CCL20 elevation. miR-143-5p injection ameliorated renal fibrosis progression in mice in vivo . Thus, targeting CCL20 by miR-143-5p could alleviate renal fibrosis progression by regulating fibroblast proliferation and ECM deposition via the Smad2/3 and AKT signaling, providing a potential therapeutic target for environmental lead contamination-evoked fibrotic kidney disease.

Transcription Factor TCF3 Promotes Macrophage-Mediated Inflammation and MMP Secretion in Abdominal Aortic Aneurysm by Regulating miR-143-5p/CCL20

“…CCL20 is a chemokine that regulates inflammation, 32 and miR-143-5p can bind with CCL20 to affect the development of renal fibrosis. 28 In this study, the miRanda algorithm predicted the binding site of homo sapiens (hsa)- miR-143-5p and CCL20, as shown in Figure 5A. The dual luciferase reporter gene system was used to verify the targeting relationship between miR-143-5p and CCL20, and the results showed that miR-143-5p significantly inhibited the luciferase activity of wild-type CCL20, but had no effect on the luciferase activity of mutant CCL20 (Fig.…”

“…27 MiR-143-5p can affect renal fibrosis by targeting CCL20. 28 However, whether targeted regulation of CCL20 by miR-143-5p is involved in the process of AAA remains unclear.…”

From Diabetic Nephropathy to End-Stage Renal Disease: The Effect of Chemokines on the Immune System

“…Marisa et al found that CXCL2 was downregulated in diabetic rats under hypoxic conditions [ 48 ]. In addition, targeting CCL20 could alleviate renal fibrosis through regulating fibroblast proliferation and suppressing collagen I expression [ 64 ].…”

Chronic heat stress induces renal fibrosis and mitochondrial dysfunction in laying hens

“…Chemokines stimulate the migration of immune cells and increase the production and activity of adhesion molecules that contribute to fibrosis and kidney damage [ 36 , 57 ]. In humans, increased expression of the IL-8 , CCL4 , and CCL20 genes are involved in the pathogenesis of renal diseases [ 58 – 60 ]. Our data showing high levels of pro-inflammatory cytokine and chemokine gene expression in heat-stressed hens indicates that the release of these cytokines contributes to the progression of renal fibrosis and failure.…”