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Twist1 regulates macrophage plasticity to promote renal fibrosis through galectin-3.

ABSTRACT: Renal interstitial fibrosis is the pathological basis of end-stage renal disease, in which the heterogeneity of macrophages in renal microenvironment plays an important role. However, the molecular mechanisms of macrophage plasticity during renal fibrosis progression remain unclear. In this study, we found for the first time that increased expression of Twist1 in macrophages was significantly associated with the severity of renal fibrosis in IgA nephropathy patients and mice with unilateral ureteral obstruction (UUO). Ablation of Twist1 in macrophages markedly alleviated renal tubular injury and renal fibrosis in UUO mice, accompanied by a lower extent of macrophage infiltration and M2 polarization in the kidney. The knockdown of Twist1 inhibited the chemotaxis and migration of macrophages, at least partially, through the CCL2/CCR2 axis. Twist1 downregulation inhibited M2 macrophage polarization and reduced the secretion of the profibrotic factors Arg-1, MR (CD206), IL-10, and TGF-β. Galectin-3 was decreased in the macrophages of the conditional Twist1-deficient mice, and Twist1 was shown to directly activate galectin-3 transcription. Up-regulation of galectin-3 recovered Twist1-mediated M2 macrophage polarization. In conclusion, Twist1/galectin-3 signaling regulates macrophage plasticity (M2 phenotype) and promotes renal fibrosis. This study could suggest new strategies for delaying kidney fibrosis in patients with chronic kidney disease.

SUBMITTER: Wu Q

PROVIDER: S-EPMC8858306 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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Twist1 regulates macrophage plasticity to promote renal fibrosis through galectin-3.

Wu Qingfeng Q Sun Shiren S Wei Lei L Liu Minna M Liu Hao H Liu Ting T Zhou Ying Y Jia Qing Q Wang Di D Yang Zhen Z Duan Menglu M Yang Xiaoxia X Gao Peisong P Ning Xiaoxuan X

Cellular and molecular life sciences : CMLS 20220219 3

Renal interstitial fibrosis is the pathological basis of end-stage renal disease, in which the heterogeneity of macrophages in renal microenvironment plays an important role. However, the molecular mechanisms of macrophage plasticity during renal fibrosis progression remain unclear. In this study, we found for the first time that increased expression of Twist1 in macrophages was significantly associated with the severity of renal fibrosis in IgA nephropathy patients and mice with unilateral uret ...[more]

PMID: 35182235

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Project description:ObjectiveTWIST1 is known to promote glycolysis and contribute to pancreatic cancer development; however, its underlying mechanisms remain poorly understood. This study aims to elucidate the molecular mechanisms by which TWIST1 influences aerobic glycolysis in pancreatic ductal adenocarcinoma (PDAC).MethodsThe expression levels of TWIST1, MMP9, MT1-MMP, and FDX1 in clinical tissues and cancer cell lines were assessed using quantitative reverse transcription PCR (QRT-PCR). Cell treatments with Elesclomol-Cu and 2-deoxyglucose (2DG) were conducted. Immunofluorescence staining and immunoprecipitation analyses were performed to investigate the binding relationship between TWIST1 and HK2. Colony formation and Transwell assays were utilized to evaluate the effects of TWIST1 on cell proliferation, migration, and invasion. Western blotting was employed to detect proteins related to cuproptosis and apoptosis, while ubiquitination assays assessed TWIST1's regulation of HK2 ubiquitination.ResultsTWIST1 expression was significantly elevated in PDAC tissues, and over-expression of TWIST1 in PDAC cells enhanced colony formation and cell proliferation. Notably, HK2 levels were markedly higher in pancreatic cancer tissues compared to adjacent normal tissues. TWIST1 was found to directly bind and interact with HK2, showing co-localization in the cytoplasm of PDAC cells. Furthermore, TWIST1 was shown to stabilize HK2 by inhibiting its ubiquitin-mediated degradation. Knockdown of TWIST1 or HK2 enhanced the inhibitory effects of 2DG on cell migration and invasion. Treatment with Elesclomol-Cu and 2DG significantly reduced the expression of the cuproptosis-related factor FDX1 with no impact on other cell death factors.ConclusionThis study demonstrates that TWIST1 regulates the ubiquitination and degradation of HK2, thereby promoting glycolysis-induced cuproptosis and facilitating pancreatic cancer invasion and metastasis. Understanding the underlying mechanisms of PDAC, including the regulation of key proteins such as HK2 by TWIST1, is crucial for developing more effective treatment strategies. Findings highlight the importance of targeting these molecular pathways, which could lead to improved diagnostic and therapeutic approaches, ultimately enhancing patient outcomes and prognosis.

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Twist1 regulates macrophage plasticity to promote renal fibrosis through galectin-3.

Publications

Twist1 regulates macrophage plasticity to promote renal fibrosis through galectin-3.

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