Klotho antagonizes pulmonary fibrosis through suppressing pulmonary fibroblasts activation, migration, and extracellular matrix production: a therapeutic implication for idiopathic pulmonary fibrosis.

Qiqing Huang,Yan Chen,Shuangshuang Wu,Liya Liu,Weihong Zhao,Wei Xu,Jianqing Wu,Yuanyuan Wang,Mingyan Lin,Shaoran Shen

doi:10.18632/aging.102978

Qiqing Huang, Yan Chen + Show 8 more

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https://doi.org/10.18632/aging.102978

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Abstract

Idiopathic pulmonary fibrosis (IPF) has been widely accepted as an aging-related fatal lung disease with a therapeutic impasse, largely a consequence of the complex and polygenic gene architecture underlying the molecular pathology of IPF. Here, by conducting an integrative network analysis on the largest IPF case-control RNA-seq dataset to date, we attributed the systems-level alteration in IPF to disruptions in a handful of biological processes including cell migration, transforming growth factor-β (TGF-β) signaling and extracellular matrix (ECM), and identified klotho (KL), a typical anti-aging molecule, as a potential master regulator of those disease-relevant processes. Following experiments showed reduced Kl in isolated pulmonary fibroblasts from bleomycin-exposed mice, and demonstrated that recombinant KL effectively mitigated pulmonary fibrosis in an ex vivo model and alleviated TGF-β-induced pulmonary fibroblasts activation, migration, and ECM production in vitro, which was partially ascribed to FOXF1 and CAV1, two highly co-expressed genes of KL in the IPF. Overall, KL appears to be a vital regulator during pulmonary fibrosis. Given that administration of exogenous KL is a feasible treatment strategy, our work highlighted a promising target gene that could be easily manipulated, leaving the field well placed to further explore the therapeutic potential of KL for IPF.

Highlights

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and fatal lung disease of unknown etiology, with a median survival time of only 2-4 years after diagnosis [1,2,3] and limited therapeutic options [4]
The subsequent experiments supported the “dry” findings by demonstrating that mouse recombinant KL (rKL) supplementation was sufficient to alleviate pulmonary fibrosis in an ex vivo model and to suppress the activation, migration, and extracellular matrix (ECM) production induced by transforming growth factor-β (TGF-β) in isolated mouse pulmonary fibroblasts
Our observation that mouse rKL along was sufficient to antagonize fibrosis in pulmonary fibroblasts is inconsistent with a recent finding that FGF23 is required for human rKL to take anti-fibrotic effect [13]

Summary

Introduction

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and fatal lung disease of unknown etiology, with a median survival time of only 2-4 years after diagnosis [1,2,3] and limited therapeutic options [4]. Despite multiple efforts have been made to evaluate the effect of KL on the reverse of hallmarks of aging lung [8], such as cellular senescence [17], mitochondrial dysfunction [16], and stem cells exhaustion [18], the molecular mechanism underlying the protective effect of KL against pulmonary fibrosis remains murky, especially KL’s regulatory role in pulmonary fibroblasts, the effector cells during the development of IPF [19]

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