BAMBI Elimination Enhances Alternative TGF-β Signaling and Glomerular Dysfunction in Diabetic Mice

Fan, Ying; Li, Xuezhu; Xiao, Wu; Fu, Jia; Harris, RC; Lindenmeyer, Maja T.; Cohen, Clemens D.; Guillot, Nicolas; Baron, Margaret H.; Wang, Niansong; Lee, Kyung Hwa; He, John Cijiang; Schlöndorff, Detlef; Chuang, Peter Y.

doi:10.2337/db14-1397

Cited by 52 publications

(51 citation statements)

References 54 publications

(105 reference statements)

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“…Reduced BAMBI expression potentiated TGF-β-induced responses. These results are in line with a previous study where TGF-β-induced α-SMA and collagen I expression was enhanced by down-regulation of BAMBI (40).…”

Section: Discussionsupporting

confidence: 93%

Fibrin fragment E potentiates TGF-β-induced myofibroblast activation and recruitment

Fuchs

Heindryckx

Calitz

et al. 2019

Preprint

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SummaryBackgroundFibrin is an essential constituent of the coagulation cascade, and the formation of hemostatic fibrin clots is central to wound healing. Fibrin clots are over time degraded into fibrin degradation products as the injured tissue is replaced by granulation tissue.Objectivesstudy the role of the fibrin degradation product fragment E (FnE) in fibroblast activation and migration.MethodsRat kidney fibroblasts (NRK-49F), human fetal lung fibroblasts (HFL1) and immortalized human foreskin fibroblasts (BJ) were exposed to FnE and TGF-β. Fibroblast activation was measured via quantitative RT-PCR and western blot for α-SMA and Collagen Iα1. A microfluidic chemotaxis assay was used to study directional migration. To investigate if FnE interacts with integrins, direct binding experiments were performed using surface plasmon resonance biosensor technology. Infusion pumps releasing FnE were implanted subcutaneously in mice and profibrotic effects of FnE were analyzed using immunohistochemical staining of the wound area.ResultsWe present evidence that FnE is a chemoattractant for fibroblasts and that FnE can potentiate TGF-β-induced myofibroblast formation. FnE forms a stable complex with αVβ3 integrin, and the integrin β3 subunit is required both for FnE-induced fibroblast migration and for potentiation of TGF-β-induced myofibroblast formation. Finally, subcutaneous infusion of FnE in mice results in a fibrotic response in the hypodermis. These results support a model where FnE released from clots in wounded tissue promote wound healing and fibrosis by both recruitment and activation of fibroblasts. Fibrin fragment E could thus represent a therapeutic target for treatment of pathological fibrosis.Essentials–Fibrin is an essential constituent of the coagulation cascade, and fibrin clotting is central to wound healing.–Fibrin clots are over time degraded into fibrin degradation products, including fibrin fragment E (FnE).–FnE is a chemoattractant for fibroblasts and can potentiate TGF-β-induced myofibroblast formation.–FnE released from clots in wounded tissue could promote wound healing and fibrosis.

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Section: Discussionsupporting

confidence: 93%

Fibrin fragment E potentiates TGF-β-induced myofibroblast activation and recruitment

Fuchs

Heindryckx

Calitz

et al. 2019

Preprint

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“…In vivo experiment showed that BAMBI transduction abolished protumor effects of an orthotopic breast cancer xenograft model (43) and modulated the effects of diabetes via inhibiting TGF-β signaling (44). Our study found that BAMBI overex pression and β-sitosterol suppressed tumor growth in NSCLC xenografts, revealing the antitumor effect of BAMBI overexpression and β-sitosterol.…”

Section: Discussionmentioning

confidence: 53%

BAMBI overexpression together with β-sitosterol ameliorates NSCLC via inhibiting autophagy and inactivating TGF-β/Smad2/3 pathway

Wang

et al. 2017

Oncology Reports

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Abstract. Non-small cell lung cancer (NSCLC) has the highest mortality rate among all solid tumors with a poor prognosis. The BMP and activin receptor membrane bound inhibitor (BAMBI) has been identified as a hallmark of NSCLC and β-sitosterol possesses antitumor potentiality. This study explores the effect of BAMBI overexpression and β-sitosterol in the context of NSCLC. The results revealed that the transfection of pcDNA-BAMBI and β-sitosterol treatment significantly reduced the levels of autophagy markers light chain 3 (LC3) II and Beclin 1, whereas the levels of LC3 I and p62 were promoted. The reduced punctate accumulations of GFP-LC3 were detected in pcDNA-BAMBI and β-sitosterol groups, especially in pcDNA-BAMBI + β-sitosterol group. BAMBI overexpression and β-sitosterol induced G0/G1 cell cycle arrest and inhibted cell proliferation in A549 cells. In addition, the levels of transforming growth factor-β (TGF-β)/p-Smad2/3/c-Myc pathway proteins were decreased. The TGF-β overexpression further confirmed that BAMBI overexpression and β-sitosterol treatment suppre ssed autohagy and viability of A549 cells was through TGF-β/Smad2/3/c-Myc pathway. Finally, the tumor growth was suppressed in NSCLC xenografts, and the inhibitory effect was stronger under treatment of pcDNA-BAMBI together with β-sitosterol. These results indicate that BAMBI overexpression and β-sitosterol may serve as novel targets for the treatment of NSCLC. IntroductionLung cancer is the leading cause of deaths with the most rapidly increasing incidence worldwide. Non-small cell lung cancer (NSCLC) has the highest mortality rate among all solid tumors with a poor prognosis (1). More than half of lung carcinomas are detected in a progressed or already metastasized state with a 5-year survival, for lacking of characteristic early symptoms (2). The general therapy treating the majority of patients is chemotherapy, which often induces resistance (3). It is necessary to develop novel therapeutic approaches to better understand the lung cancer progression.Autophagy is a fundamental cellular homeostatic process that cells use to degrade and recycle cellular proteins (4). This process can be induced in response to either intracellular or extracellular factors, such as hypoxia, low cellular energy state and organelle damage (5). The microtubule-associated protein 1 light chain 3 (LC3), functions as a structural component in the formation of autophagosomes. The conversion of the cytosolic form of LC3 (LC3 I) to lipidated form (LC3 II) indicates autophagosome formation (6). Beclin 1, is required for the initiation and in the process of autophagosome formation (7). p62 acts as a receptor or adaptor for autophagic degradation of ubiquitinated proteins, the upregulation of p62 is commonly detected in human tumors and contributes dire ctly to tumorigenesis (8). Thus, LC3, Beclin 1 and p62 were considered as autophagy markers in many studies (9,10).Transforming growth factor-β (TGF-β) has a crucial role in homeostasis, fibrosis angiogenesis, carcinogenesis and d...

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“…Fig. 2) [24]. These mRNA (UMOD, SLC12A1, NDUFB2, OAZ1, PPARGC1A, NFE2L2, CD24, SMAD1) were selected for qPCR screening and validation in this larger study described here.…”

Section: Resultsmentioning

confidence: 99%

Uromodulin mRNA from Urinary Extracellular Vesicles Correlate to Kidney Function Decline in Type 2 Diabetes Mellitus

Yamamoto¹,

Murakami²,

Oakes³

et al. 2018

Am J Nephrol

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Background: Extracellular vesicles (EVs) enclose mRNA derived from their cell of origin and are considered a source of potential biomarkers. We examined urinary EV mRNA from individuals with diabetic kidney disease (DKD), chronic kidney disease, type 2 diabetes (T2DM), and obese and healthy controls to determine if such biomarkers had the potential to classify kidney disease and predict patients at higher risk of renal function decline. Methods: A total of 242 participants enrolled in this study. Urinary EV mRNA from all subjects were isolated by a filter-based platform, and the expression of 8 target genes were determined by quantitative polymerase chain reaction (qPCR). Changes in estimated glomerular filtration rate (eGFR) in 161 T2DM patients were evaluated for 2 consecutive years and compared with EV RNA profiles at baseline. Results: We observe that mild and severe DKD groups show a significant 3.2- and 4.4-fold increase in UMOD compared to healthy controls and expression increases linearly from healthy, diabetic, and DKD subjects. UMOD expression is significantly correlated to albumin creatinine ratio (ACR), eGFR, and HbA1c. Using linear discriminant analyses with mRNA from severe DKD and T2DM as training data, a multi-gene signature classified DKD and non-DKD with a sensitivity of 93% and specificity of 73% with area under the receiver operating characteristic (ROC) curve (AUC) = 0.90. Although 6% of T2DM were determined to have a > 80% posterior probability of developing DKD based on this mRNA profile, eGFR changes observed within the 2-year follow-up did not reveal a decline in kidney function. Conclusion: Urinary EV UMOD mRNA levels are progressively elevated from T2DM to DKD groups and correlate with widely used eGFR and ACR diagnostic criteria. An EV mRNA signature could identify DKD with greater than 90% sensitivity and 70% specificity.

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BAMBI Elimination Enhances Alternative TGF-β Signaling and Glomerular Dysfunction in Diabetic Mice

Cited by 52 publications

References 54 publications

Fibrin fragment E potentiates TGF-β-induced myofibroblast activation and recruitment

Fibrin fragment E potentiates TGF-β-induced myofibroblast activation and recruitment

BAMBI overexpression together with β-sitosterol ameliorates NSCLC via inhibiting autophagy and inactivating TGF-β/Smad2/3 pathway

Uromodulin mRNA from Urinary Extracellular Vesicles Correlate to Kidney Function Decline in Type 2 Diabetes Mellitus

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