Research Paper Volume 12, Issue 7 pp 5812—5831

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

Qiqing Huang 1, *, , Yan Chen 1, *, , Shaoran Shen 1, , Yuanyuan Wang 2, , Liya Liu 2, , Shuangshuang Wu 1, , Wei Xu 1, , Weihong Zhao 1, , Mingyan Lin 2, , Jianqing Wu 1, ,

  • 1 Key Laboratory of Geriatrics of Jiangsu Province, Department of Geriatrics, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu, China
  • 2 Department of Neurobiology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing 211166, Jiangsu, China
* Equal contribution

received: November 21, 2019 ; accepted: February 5, 2020 ; published: April 3, 2020 ;

https://doi.org/10.18632/aging.102978
How to Cite

Copyright © 2020 Huang et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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.

Abbreviations

IPF: Idiopathic pulmonary fibrosis; KL: Klotho; WGCNA: Weighted Gene Co-expression network analysis; PCLSs: Precision-cut lung slices; TGF-β: Transforming growth factor-β; ECM: Extracellular matrix; rKL: Recombinant klotho; α-SMA: α-smooth muscle actin; FC: Fibrotic cocktail; CC: Control cocktail; TNF-α: Tumor necrosis factor-α; PDGF-AB: Platelet-derived growth factor-AB; LPA: Lysophosphatidic acid; Fn1: Fibronectin; Col1a1: Collagen I; EndoMT: Endothelial-mesenchymal transition; BLM: Bleomycin; FOXF1: forkhead box F1; CAV1: caveolin 1; CDH2: cadherin 2; CDH11: cadherin 11; Erk1/2: extracellular signal-regulated kinase1/2; JNK: c-Jun NH2-terminal kinase.