Axl‐inhibitor bemcentinib alleviates mitochondrial dysfunction in the unilateral ureter obstruction murine model

Hoel, August; Osman, Tarig Al-Hadi; Hoel, Fredrik; Elsaid, Hassan Osman Alhassan; Chen, Tony; Landolt, Lea; Babickova, Janka; Tronstad, Karl Johan; Lorens, James B.; Gausdal, Gro; Marti, Hanspeter; Furriol, Jessica

doi:10.1111/jcmm.16769

Cited by 12 publications

(10 citation statements)

References 48 publications

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“…The UUO model was established as described in previous study (Hoel et al, 2021). Briefly, the flank was exposed via a midline incision in the under aseptic conditions, the left ureter was exposed and ligated.…”

Section: Unilateral Ureteral Occlusion Model and In Vivo Shrna Treatmentmentioning

confidence: 99%

Targeting Mechanosensitive Piezo1 Alleviated Renal Fibrosis Through p38MAPK-YAP Pathway

Wan

Zhang

et al. 2021

Front. Cell Dev. Biol.

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Renal fibrosis is the most common pathological manifestation of a wide variety of chronic kidney disease. Increased extracellular matrix (ECM) secretion and enhanced microenvironment stiffening aggravate the progression of renal fibrosis. However, the related mechanisms remain unclear. Here, we evaluated the mechanism by which ECM stiffness aggravates renal fibrosis. In the present study, renal mesangial cells (MCs) were cultured on polyacrylamide hydrogels with different stiffness accurately detected by atomic force microscope (AFM), simulating the in vivo growth microenvironment of MCs in normal kidney and renal fibrosis. A series of in vitro knockdown and activation experiments were performed to establish the signaling pathway responsible for mechanics-induced MCs activation. In addition, an animal model of renal fibrosis was established in mice induced by unilateral ureteral obstruction (UUO). Lentiviral particles containing short hairpin RNA (sh RNA) targeting Piezo1 were used to explore the effect of Piezo1 knockdown on matrix stiffness-induced MCs activation and UUO-induced renal fibrosis. An in vitro experiment demonstrated that elevated ECM stiffness triggered the activation of Piezo1, which increased YAP nuclear translocation through the p38MAPK, and consequently led to increased ECM secretion. Furthermore, these consequences have been verified in the animal model of renal fibrosis induced by UUO and Piezo1 knockdown could alleviate UUO-induced fibrosis and improve renal function in vivo. Collectively, our results for the first time demonstrate enhanced matrix stiffness aggravates the progression of renal fibrosis through the Piezo1-p38MAPK-YAP pathway. Targeting mechanosensitive Piezo1 might be a potential therapeutic strategy for delaying the progression of renal fibrosis.

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Section: Unilateral Ureteral Occlusion Model and In Vivo Shrna Treatmentmentioning

confidence: 99%

Targeting Mechanosensitive Piezo1 Alleviated Renal Fibrosis Through p38MAPK-YAP Pathway

Wan

Zhang

et al. 2021

Front. Cell Dev. Biol.

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“…Renal fibrosis is a common pathological feature of progressive CKD [ 27 ], and clinical management of renal fibrosis remains challenging, which is in part attributed to the lack of effective drugs. Accumulative evidence reveals an important role of mitochondrial damage in renal fibrosis, such as IRI and urinary obstruction [ 6 , 7 ]. AKF-PD displays antirenal fibrosis activities [ 28 , 29 ].…”

Section: Discussionmentioning

confidence: 99%

“…Although mitochondrial damage has been reported in the UUO and IRI models [ 6 , 7 ], the characteristics of mitochondrial damage in the two renal fibrosis models remained vague because of the complexity of the injuring mechanism. Our results suggested that impaired TCA cycle and mitochondrial respiratory chain as well as inhibited TRX2 expression and SIRT3/SOD2 signaling pathway contributed to mitochondrial damage in the UUO and IRI models.…”

Section: Discussionmentioning

confidence: 99%

“…Clinically, renal fibrosis can be resulted from complex mechanisms related to a variety of kidney injuries, such as urinary obstruction and ischemia [ 3 , 4 ]; both disease courses are commonly modeled by unilateral ureteral obstruction (UUO) and ischemia-reperfusion injury (IRI) procedures [ 5 ]. The mechanisms leading to renal fibrosis in both animal models (UUO and IRI) are likely complex; accumulative evidence reveals mitochondrial damage as a pathological cause [ 6 , 7 ]. In the UUO and IRI models, renal fibrosis is progressed along with mitochondrial damage, evident by disrupted energy metabolism, impaired mitochondrial biogenesis, and oxidative stress [ 8 , 9 ].…”

Section: Introductionmentioning

confidence: 99%

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Fluorofenidone Inhibits UUO/IRI-Induced Renal Fibrosis by Reducing Mitochondrial Damage

Liao

Zhang

et al. 2022

Oxidative Medicine and Cellular Longevity

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Objective. Mitochondrial damage contributes to extracellular matrix (ECM) deposition and renal fibrosis. In this study, we aimed (1) to investigate whether fluorofenidone (AKF-PD) can attenuate mitochondrial damage in two renal fibrosis models: unilateral ureteral obstruction (UUO) and renal ischemia-reperfusion injury (IRI), and (2) to explore the underlying mechanism. Method. Mitochondrial damage and renal lesions were analyzed in the UUO and IRI models. Mitochondrial energy metabolism, mitochondrial biogenesis, and oxidative stress were measured to assess the effect of AKF-PD on mitochondrial damage and to explore the underlying mechanism. In addition, HK-2 cells were stimulated with TGF-β with and without AKF-PD. The mitochondrial morphology, mtROS, ATP contents, and redox-related proteins were then examined. Results. In both UUO and IRI models, AKF-PD relieved renal fibrosis, maintained mitochondrial structure, and increased mitochondrial DNA copy numbers. The protection was associated with (1) sustaining mitochondrial energy metabolism, evident by elevations of tricarboxylic acid (TCA) cycle enzymes and mitochondrial respiratory chain complexes; (2) improving mitochondrial biogenesis with increases of TFAM, NRF1, PGC-1α, and SIRT1; and (3) reducing mitochondrial oxidative stress likely via regulating SOD2, SIRT3, and NOX4 expressions. In HK-2 cells treated with TGF-β, AKF-PD protected mitochondria along with improving mitochondrial morphology, enhancing ATP production, reducing mtROS, and regulating SOD2, SIRT3, and NOX4 expression. Conclusion. We demonstrate that AKF-PD inhibited renal fibrosis at least in part via protecting mitochondria from damages developed in the UUO and IRI models. The mitochondrial protection was associated with sustaining mitochondrial energy metabolism, improving mitochondrial biogenesis, and reducing mitochondrial oxidative stress. This research verified the protective effect of AKF-PD on mitochondria in the UUO and IRI models and elaborated the underlying mechanism.

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“…accordance, recent studies have shown that the strategies for improving mitochondrial integrity and function are capable of alleviating AKI (Guan et al, 2021;Hoel et al, 2021;Z. Li et al, 2021;Miguel et al, 2021).…”

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confidence: 99%

Overexpression of NDUFV1 alleviates renal damage by improving mitochondrial function in unilateral ureteral obstruction model mice

Wang

Chen

et al. 2022

Cell Biology International

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Mitochondrial homeostasis plays essential role for the proper functioning of the kidney. NADH‐ubiquinone oxidoreductase core subunit V1 (NDUFV1) is an enzyme in the complex I of electron transport chain (ETC) in mitochondria. In the present study, we examined the effects of NDUFV1 on renal function in unilateral ureteral obstruction (UUO) model mice. Our data showed that increased expression of NDUFV1 improves kidney function as evidenced by the decreases in blood urea nitrogen and serum creatinine in UUO mice. Moreover, NDUFV1 also maintains renal structures and alleviates renal fibrosis induced by UUO surgery. Mechanistically, NDUFV1 mitigates the increased oxidative stress in the kidney in UUO model mice. Meanwhile, increased expression of NDUFV1 in the kidney improves the integrity of the complex I and potentiates the complex I activity. Overall, these results indicate that the ETC complex I plays a beneficial role against renal dysfunction induced by acute kidney injury such as UUO. Therefore, NDUFV1 might be a druggable target for developing agents for dealing with disabled mitochondria‐associated renal diseases.

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Axl‐inhibitor bemcentinib alleviates mitochondrial dysfunction in the unilateral ureter obstruction murine model

Cited by 12 publications

References 48 publications

Targeting Mechanosensitive Piezo1 Alleviated Renal Fibrosis Through p38MAPK-YAP Pathway

Targeting Mechanosensitive Piezo1 Alleviated Renal Fibrosis Through p38MAPK-YAP Pathway

Fluorofenidone Inhibits UUO/IRI-Induced Renal Fibrosis by Reducing Mitochondrial Damage

Overexpression of NDUFV1 alleviates renal damage by improving mitochondrial function in unilateral ureteral obstruction model mice

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