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

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 (<i>KL</i>), a typical anti-aging molecule, as a potential master regulator of those disease-relevant processes. Following experiments showed reduced <i>Kl</i> in isolated pulmonary fibroblasts from bleomycin-exposed mice, and demonstrated that recombinant KL effectively mitigated pulmonary fibrosis in an <i>ex vivo</i> model and alleviated TGF-β-induced pulmonary fibroblasts activation, migration, and ECM production <i>in vitro</i>, which was partially ascribed to <i>FOXF1</i> and <i>CAV1</i>, two highly co-expressed genes of <i>KL</i> in the IPF. Overall, <i>KL</i> 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 <i>KL</i> for IPF.