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 (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.

Klotho Modulates Pro-Fibrotic Activities in Human Atrial Fibroblasts through Inhibition of Phospholipase C Signaling and Suppression of Store-Operated Calcium Entry

“…In addition, fibrosis decelerates action potential propagation and enhances ectopic automaticity, contributing to arrhythmogenesis [ 3 , 33 ]. Klotho is a type 1 single-pass transmembrane protein with pleiotropic functions, including attenuating pro-fibrotic response [ 8 , 11 , 12 , 13 , 34 , 35 , 36 ]. Initially, Klotho was found to ameliorate renal fibrosis [ 37 ]; however, emerging evidence suggests that Klotho attenuates fibrosis in extra-renal tissues, such as pulmonary and cardiovascular systems [ 8 , 13 ].…”

“…In addition, fibrosis decelerates action potential propagation and enhances ectopic automaticity, contributing to arrhythmogenesis [3,33]. Klotho is a type 1 single-pass transmembrane protein with pleiotropic functions, including attenuating pro-fibrotic response [8,[11][12][13][34][35][36]. Initially, Klotho was found to (C) Fibroblasts in the control group had higher peak inward currents and outward currents than the other 3 groups (n = 14-18 from 5-7 independent experiments).…”

“…Several studies demonstrated that Klotho regulates transient receptor potential (TRP) channels to protect the cardiovascular system and maintain its integrity [ 5 , 9 , 10 ]. Additionally, Klotho was reported to suppress pulmonary and renal fibrosis [ 11 , 12 , 13 ]. However, knowledge of the role of Klotho in atrial fibrosis is limited.…”

Constitutive transgenic α-Klotho overexpression enhances resilience to and recovery from murine acute lung injury

“…Exogenous Klotho reduces mortality in murine paraquat-induced ALI by inhibiting ROS/P38 MAPK-regulated inflammatory cytokines and mitochondria-dependent apoptosis (49). Klotho regulates ion channel transporters and ion-translocating ATPase (53) that mediate lung salt and water balance in ALI ( 54) and suppresses pulmonary fibrosis by inhibiting fibroblasts activation, migration, and extracellular matrix production (50). In human subjects with interstitial lung abnormalities, lower serum Klotho levels are associated with reduced lung function (55).…”

Orally-active, clinically-translatable senolytics restore α-Klotho in mice and humans

“…Transgenic mice overexpressing α-Klotho are protected from Bleomycin-induced pulmonary fibrosis. 46 , 47 Patients with IPF have decreased plasma α-Klotho 48 as well as an increased burden of senescent cells. 45 α-Klotho is lower in lung fibroblasts cultured from IPF patients than control subjects without IPF.…”