Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease with multiple causes, characterized by excessive myofibrocyte aggregation and extracellular matrix deposition. Related studies have shown that transforming growth factor-β1 (TGF-β1) is a key cytokine causing fibrosis, promoting abnormal epithelial–mesenchymal communication and fibroblast-to-myofibroblast transition. Fedratinib (Fed) is a marketed drug for the treatment of primary and secondary myelofibrosis, targeting selective JAK2 tyrosine kinase inhibitors. However, its role in pulmonary fibrosis remains unclear. In this study, we investigated the potential effects and mechanisms of Fed on pulmonary fibrosis in vitro and in vivo. In vitro studies have shown that Fed attenuates TGF-β1- and IL-6-induced myofibroblast activation and inflammatory response by regulating the JAK2/STAT3 signaling pathway. In vivo studies have shown that Fed can reduce bleomycin-induced inflammation and collagen deposition and improve lung function. In conclusion, Fed inhibited inflammation and fibrosis processes induced by TGF-β1 and IL-6 by targeting the JAK2 receptor.
Circadian clock is involved in regulating most renal physiological functions, including water and electrolyte balance and blood pressure homeostasis, however, the role of circadian clock in renal pathophysiology remains largely unknown. Here we aimed to investigate the role of Bmal1, a core clock component, in the development of renal fibrosis, the hallmark of pathological features in many renal diseases. The inducible Bmal1 knockout mice (iKO) whose gene deletion occurred in adulthood were used in the study. Analysis of the urinary water, sodium and potassium excretion showed that the iKO mice exhibit abolished diurnal variations. In the model of renal fibrosis induced by unilateral ureteral obstruction, the iKO mice displayed significantly decreased tubulointerstitial fibrosis reflected by attenuated collagen deposition and mitigated expression of fibrotic markers α-SMA and fibronectin. The hedgehog pathway transcriptional effectors Gli1 and Gli2, which have been reported to be involved in the pathogenesis of renal fibrosis, were significantly decreased in the iKO mice. Mechanistically, ChIP assay and luciferase reporter assay revealed that BMAL1 bound to the promoter of and activate the transcription of Gli2, but not Gli1, suggesting that the involvement of Bmal1 in renal fibrosis was possibly mediated via Gli2-dependent mechanisms. Furthermore, treatment with TGF-β increased Bmal1 in cultured murine proximal tubular cells. Knockdown of Bmal1 abolished, while overexpression of Bmal1 increased, Gli2 and the expression of fibrosis-related genes. Collectively, these results revealed a prominent role of the core clock gene Bmal1 in tubulointerstitial fibrosis. Moreover, we identified Gli2 as a novel target of Bmal1, which may mediate the adverse effect of Bmal1 in obstructive nephropathy.
Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease, and the molecular mechanisms remain poorly understood. Our findings demonstrated that pyruvate kinase M2 (PKM2) promoted fibrosis progression by directly interacting with Smad7 and reinforcing transforming growth factor–β1 (TGF-β1) signaling. Total PKM2 expression and the portion of the tetrameric form elevated in lungs and fibroblasts were derived from mice with bleomycin (BLM)–induced pulmonary fibrosis. Pkm2 deletion markedly alleviated BLM-induced fibrosis progression, myofibroblast differentiation, and TGF-β1 signaling activation. Further study showed that PKM2 tetramer enhanced TGF-β1 signaling by directly binding with Smad7 on its MH2 domain, and thus interfered with the interaction between Smad7 and TGF-β type I receptor (TβR1), decreased TβR1 ubiquitination, and stabilized TβR1. Pharmacologically enhanced PKM2 tetramer by TEPP-46 promoted BLM-induced pulmonary fibrosis, while tetramer disruption by compound 3k alleviated fibrosis progression. Our results demonstrate how PKM2 regulates TGF-β1 signaling and is a key factor in fibrosis progression.
Background Mice with cardiomyocyte‐specific deletion of Bmal1, a core clock gene, had spontaneous abnormal cardiac metabolism, dilated cardiomyopathy, and shortened lifespan. However, the role of cardiomyocyte Bmal1 in pressure overload induced cardiac remodeling is unknown. Here we aimed to understand the contribution of cardiomyocyte Bmal1 to cardiac remodeling in response to pressure overload induced by transverse aortic constriction or chronic angiotensin Ⅱ (AngⅡ) infusion. Methods and Results By generating a tamoxifen‐inducible cardiomyocyte‐specific Bmal1 knockout mouse line (cKO) and challenging the mice with transverse aortic constriction or AngⅡ, we found that compared to littermate controls, the cKO mice displayed remarkably increased cardiac hypertrophy and augmented fibrosis both after transverse aortic constriction and AngⅡ induction, as assessed by echocardiographic, gravimetric, histologic, and molecular analyses. Mechanistically, RNA‐sequencing analysis of the heart after transverse aortic constriction exposure revealed that the PI3K/AKT signaling pathway was significantly activated in the cKOs. Consistent with the in vivo findings, in vitro study showed that knockdown of Bmal1 in cardiomyocytes significantly promoted phenylephrine‐induced cardiomyocyte hypertrophy and triggered fibroblast‐to‐myofibroblast differentiation, while inhibition of AKT remarkedly reversed the pro‐hypertrophy and pro‐fibrosis effects of Bmal1 knocking down. Conclusions These results suggest that postnatal deletion of Bmal1 in cardiomyocytes may promote pressure overload‐induced cardiac remodeling. Moreover, we identified PI3K/AKT signaling pathway as the potential mechanistic ties between Bmal1 and cardiac remodeling.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.