Esaxerenone Inhibits Renal Angiogenesis and Endothelial-Mesenchymal Transition via the VEGFA and TGF-β1 Pathways in Aldosterone-Infused Mice

Gao, Xiaomeng; Chang, Jungshan; Chang, Yi; Fan, Lili; Liu, Ziqian; Zhang, Cuijuan; Shimosawa, Tatsuo; Yang, Fan; Xu, Qingyou

doi:10.3390/ijms241411766

Cited by 3 publications

(1 citation statement)

References 47 publications

(57 reference statements)

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“…Esaxerenone, which is a new non-steroidal MR antagonist, improves endothelial dysfunction caused by diabetes by promoting eNOS phosphorylation in the DCM group [5,6]. Several clinical studies have reported that esaxerenone has significant antihypertensive and cardiorenal protective effects compared with spironolactone and eplerenone [7,8]. Pharmacological studies have shown that due to its inverted side-chain structure, esaxerenone has an affinity for MRs that is over 1000 times higher than other NR3C nuclear receptors.…”

Section: Introductionmentioning

confidence: 99%

Esaxerenone Protects against Diabetic Cardiomyopathy via Inhibition of the Chemokine and PI3K-Akt Signaling Pathway

Li,

Zhang,

Zheng

et al. 2023

Biomedicines

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(1) Background: Diabetic cardiomyopathy (DCM) is a unique form of cardiomyopathy that develops as a consequence of diabetes and significantly contributes to heart failure in patients. Esaxerenone, a selective non-steroidal mineralocorticoid receptor antagonist, has demonstrated potential in reducing the incidence of cardiovascular and renal events in individuals with chronic kidney and diabetes disease. However, the exact protective effects of esaxerenone in the context of DCM are still unclear. (2) Methods: The DCM model was successfully induced in mice by administering streptozotocin (55 mg/kg per day) for five consecutive days. After being fed a normal diet for 16 weeks, echocardiography was performed to confirm the successful establishment of the DCM model. Subsequent sequencing and gene expression analysis revealed significant differences in gene expression in the DCM group. These differentially expressed genes were identified as potential targets for DCM. By utilizing the Swiss Target Prediction platform, we employed predictive analysis to identify the potential targets of esaxerenone. A protein–protein-interaction (PPI) network was constructed using the common targets of esaxerenone and DCM. Enrichment analysis was conducted using Metascape. (3) Results: Compared to the control, the diabetic group exhibited impaired cardiac function and myocardial fibrosis. There was a total of 36 common targets, with 5 key targets. Enrichment analysis revealed that the chemokine and PI3K-Akt signaling pathway was considered a crucial pathway. A target-pathway network was established, from which seven key targets were identified. All key targets exhibited good binding characteristics when interacting with esaxerenone. (4) Conclusion: The findings of this study suggest that esaxerenone exhibits a favorable therapeutic effect on DCM, primarily by modulating the chemokine and PI3K-Akt signaling pathway.

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Section: Introductionmentioning

confidence: 99%

Esaxerenone Protects against Diabetic Cardiomyopathy via Inhibition of the Chemokine and PI3K-Akt Signaling Pathway

Li,

Zhang,

Zheng

et al. 2023

Biomedicines

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Cyanoacrylate Adhesives for Cutaneous Wound Closure

Viana,

Di Filippo,

Gobbi

et al. 2024

Animals

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Cyanoacrylate-based adhesives are widely used in wound closure, providing good cosmetic results and little discomfort. However, reports in the literature are found about negative effects that include the release of cytotoxic chemicals during biodegradation. In this study, we sought to evaluate and compare the effectiveness of four cyanoacrylate-based adhesives on the closure of skin incisions in Rattus norvegicus. The animals (n = 140) were divided into five groups of 28 animals each according to the wound closure technique: G1 and G2 (n-2-ethyl-cyanoacrylate); G3 (n-2-butyl-cyanoacrylate); G4 (n-2-octyl-cyanoacrylate); and G5 (5 nylon stitches). Midline incisions measuring 5.0 cm in length were created and closed using the different materials evaluated, and on D3, D7, D14, and D21, tensiometric and histopathological analyses were performed. Shorter wound closure and adhesion times were observed in G4 animals. At D3 and D7, G5 presented greater tensiometric resistance in the animals of G5, with a decrease in D14 and D21 compared to the other groups. On the other hand, the wounds of G3 and G4 were more resistant in D14 and D21, reaching maximum resistance values. Polymorphonuclear and mononuclear cells are more prevalent and more granulation tissue was observed in G5. The deposition of type III collagen was more evident in G5, whilst there was no difference in the amount of type I collagen in any of the groups treated with cyanoacrylate adhesives. Larger areas stained positive for VEGF-α in G2 and smaller areas in G4, with peaks at D7 and D14. In general, cyanoacrylate adhesives cause less intense inflammatory reactions, resulting in shorter healing times when compared to nylon sutures.

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Esaxerenone Attenuates Aldosterone-Induced Mitochondrial Damage-Mediated Pyroptosis in Mouse Aorta and Rat Vascular Smooth Muscle Cells

Xian,

Wang,

Chang

et al. 2024

Life

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Background: Vascular smooth muscle cell (VSMC) injury caused by the inflammatory response plays a key role in cardiovascular disease (CVD), and the vasoprotective effects of mineralocorticoid receptor blockers (MRBs) support the role of mineralocorticoid receptor (MR) activation. Methods: C57BL/6 mice and VSMCs isolated from rats were treated with aldosterone and esaxerenone. Caspase-1, GSDMD-N, IL-1β, and NR3C2 expression and DNA damage in aortic VSMCs were detected using immunohistochemistry, Western blotting, and TUNEL staining. Mitochondrial changes were detected by transmission electron microscopy (TEM). Reactive oxygen species (ROS), MitoTracker, JC-I, mitochondrial respiratory chain complexes I–V, and NR3C2 were detected using immunofluorescence and flow cytometry. Pyroptosis was detected with scanning electron microscopy (SEM). Results: After aldosterone treatment, the number of TUNEL-positive cells increased significantly, and the expression of caspase-1, GSDMD-N, and IL-1β increased. TEM revealed mitochondrial damage, and SEM revealed specific pyroptotic changes, such as cell membrane pore changes and cytoplasmic extravasation. Increased ROS levels and nuclear translocation of NR3C2 were also observed. These pyroptosis-related changes were reversed by esaxerenone. Conclusions: Aldosterone activates the MR and mediates mitochondrial damage, thereby inducing pyroptosis in VSMCs via the NLRP3/caspase-1 pathway. Esaxerenone inhibits MR activation and reduces mitochondrial damage and oxidative stress, thereby inhibiting pyroptosis.

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Esaxerenone Inhibits Renal Angiogenesis and Endothelial-Mesenchymal Transition via the VEGFA and TGF-β1 Pathways in Aldosterone-Infused Mice

Cited by 3 publications

References 47 publications

Esaxerenone Protects against Diabetic Cardiomyopathy via Inhibition of the Chemokine and PI3K-Akt Signaling Pathway

Esaxerenone Protects against Diabetic Cardiomyopathy via Inhibition of the Chemokine and PI3K-Akt Signaling Pathway

Cyanoacrylate Adhesives for Cutaneous Wound Closure

Esaxerenone Attenuates Aldosterone-Induced Mitochondrial Damage-Mediated Pyroptosis in Mouse Aorta and Rat Vascular Smooth Muscle Cells

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