Role of fibroblast growth factor 23 and klotho cross talk in idiopathic pulmonary fibrosis

• Published in: American journal of physiology. Lung cellular and molecular physiology 2019-07, Vol.317 (1), p.L141-L154
• Main Authors: Barnes, Jarrod W, Duncan, Dawn, Helton, Scott, Hutcheson, Samuel, Kurundkar, Deepali, Logsdon, Naomi J, Locy, Morgan, Garth, Jaleesa, Denson, Rebecca, Farver, Carol, Vo, Hai T, King, Gwendalyn, Kentrup, Dominik, Faul, Christian, Kulkarni, Tejaswini, De Andrade, Joao A, Yu, Zhihong, Matalon, Sadis, Thannickal, Victor J, Krick, Stefanie
• Format: Article
• Language: English
• Subjects: Acute Lung Injury - chemically induced; Acute Lung Injury - genetics; Acute Lung Injury - immunology; Acute Lung Injury - pathology; Age related diseases; Aged; Aging; Animal tissues; Animals; Anti-inflammatory agents; Bleomycin; Bleomycin - administration & dosage; Blood plasma; Case-Control Studies; Collagen; Collagen - antagonists & inhibitors; Collagen - genetics; Collagen - metabolism; Crosstalk; Female; Fibroblast Growth Factor-23; Fibroblast Growth Factors - genetics; Fibroblast Growth Factors - metabolism; Fibroblast Growth Factors - pharmacology; Fibroblasts; Fibroblasts - drug effects; Fibroblasts - metabolism; Fibroblasts - pathology; Fibrosis; Gene Expression Regulation; Geriatrics; Glucuronidase - genetics; Glucuronidase - metabolism; Glucuronidase - pharmacology; Growth factors; Humans; Idiopathic Pulmonary Fibrosis - genetics; Idiopathic Pulmonary Fibrosis - metabolism; Idiopathic Pulmonary Fibrosis - pathology; Inflammation; Kidney Function Tests; Klotho protein; Klotho Proteins; Lung - drug effects; Lung - metabolism; Lung - pathology; Lung diseases; Lungs; Male; Mice; Mice, Transgenic; Middle Aged; Older people; Oxidative stress; Primary Cell Culture; Pulmonary fibrosis; Respiratory Function Tests; Restoration; Senescence; Signal Transduction - genetics; Transforming growth factor; Transforming Growth Factor beta - antagonists & inhibitors; Transforming Growth Factor beta - pharmacology; Transforming growth factor-b; Transgenic mice
• ISSN: 1040-0605; 1522-1504
• DOI: 10.1152/ajplung.00246.2018

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrosing interstitial pneumonia that mainly affects the elderly. Several reports have demonstrated that aging is involved in the underlying pathogenic mechanisms of IPF. α-Klotho (KL) has been well characterized as an "age-suppressing" hormone and can provide protection against cellular senescence and oxidative stress. In this study, KL levels were assessed in human plasma and primary lung fibroblasts from patients with idiopathic pulmonary fibrosis (IPF-FB) and in lung tissue from mice exposed to bleomycin, which showed significant downregulation when compared with controls. Conversely, transgenic mice overexpressing KL were protected against bleomycin-induced lung fibrosis. Treatment of human lung fibroblasts with recombinant KL alone was not sufficient to inhibit transforming growth factor-β (TGF-β)-induced collagen deposition and inflammatory marker expression. Interestingly, fibroblast growth factor 23 (FGF23), a proinflammatory circulating protein for which KL is a coreceptor, was upregulated in IPF and bleomycin lungs. To our surprise, FGF23 and KL coadministration led to a significant reduction in fibrosis and inflammation in IPF-FB; FGF23 administration alone or in combination with KL stimulated KL upregulation. We conclude that in IPF downregulation of KL may contribute to fibrosis and inflammation and FGF23 may act as a compensatory antifibrotic and anti-inflammatory mediator via inhibition of TGF-β signaling. Upon restoration of KL levels, the combination of FGF23 and KL leads to resolution of inflammation and fibrosis. Altogether, these data provide novel insight into the FGF23/KL axis and its antifibrotic/anti-inflammatory properties, which opens new avenues for potential therapies in aging-related diseases like IPF.