Abstract
Liver fibrosis, the common response associated with chronic liver diseases, ultimately leads to cirrhosis, a major public health problem worldwide. Activation of hepatic stellate cells (HSCs) by transforming growth factor (TGF)-β1 is a key step in liver fibrosis. Here we report that Kindlin-2 expression is elevated in the livers of mice with experimental liver fibrosis and also in the livers of patients with liver fibrosis. TGF-β1 increases Kindlin-2 expression in cultured HSCs in a p38 and ERK mitogen-activated protein kinase (MAPK)-dependent manner, partly. More importantly, Kindlin-2 deficiency significantly attenuated mouse liver fibrosis and HSC activation. Mechanistically, Kindlin-2 promotes TGF-β signaling through upregulation of Smad2 and Smad3 phosphorylation. Our work demonstrates an important role for Kindlin-2 in liver fibrosis, and inhibiting Kindlin-2 in the livers may represent a novel strategy to treat liver fibrosis.
Highlights
Liver fibrosis is a tightly controlled wound healing response to virtually all forms of chronic liver injury due to viral infections, metabolic, and autoimmune diseases, which results in excessive accumulation of extracellular matrix (ECM) and impaired normal liver function[1]
We showed that Kindlin-2 is upregulated in human and mouse fibrotic livers, and this upregulation is mediated by Transforming growth factor (TGF)-β1 through noncanonical Smad pathways in hepatic stellate cells (HSCs), and enhances HSC activation
We demonstrated that the TGF-β1 triggers Kindlin-2 expression via p38 and extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) pathway
Summary
Liver fibrosis is a tightly controlled wound healing response to virtually all forms of chronic liver injury due to viral infections, metabolic, and autoimmune diseases, which results in excessive accumulation of extracellular matrix (ECM) and impaired normal liver function[1]. It is widely accepted that activated hepatic stellate cells (HSCs) play a pivotal role during development of liver fibrosis[2]. In response to liver injury, quiescent HSCs activate and differentiate into myofibroblast-like cells that are fibrogenic, contractile, and proliferative[2,3]. Transforming growth factor (TGF)-β1 has been identified as the most potent mediator of HSC activation in liver fibrosis among several growth factors and cytokines[4]. GTPase signaling pathways, and phosphatidylinositol-3kinase (PI3K)/AKT pathways[7]. Both canonical and noncanonical pathways have been linked to HSC activation and liver fibrosis[8]
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