Mitochondrial dysfunction and endoplasmic reticulum stress in the promotion of fibrosis in obstructive nephropathy induced by unilateral ureteral obstruction

Martínez-Klimova, Elena; Aparicio-Trejo, Omar Emiliano; Gómez-Sierra, Tania; Jiménez-Uribe, Alexis Paulina; Bellido, Belén; Pedraza‐Chaverrí, José

doi:10.1002/biof.1673

Cited by 46 publications

(58 citation statements)

References 148 publications

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“…Although accumulated evidence suggests that mitochondrial fission and oxidative stress participate in CKD progression [ 41 , 42 ], there have been only limited studies on whether reducing mitochondrial fission and ROS production in podocytes by pharmacological approaches could reduce kidney damage. The application of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin-receptor blockers (ARBs) in CKD patients leads to partial relief of oxidative stress in the kidney [ 7 ], and the effects of antioxidant interventions targeting the level of total cellular redox status are disappointing, since traditional antioxidants are not well taken up by mitochondria.…”

Section: Discussionmentioning

confidence: 99%

Mitoquinone Protects Podocytes from Angiotensin II‐Induced Mitochondrial Dysfunction and Injury via the Keap1‐Nrf2 Signaling Pathway

Zhu

Liang

Chen

et al. 2021

Oxidative Medicine and Cellular Longevity

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Podocyte mitochondrial dysfunction plays a critical role in the pathogenesis of chronic kidney disease (CKD). Previous studies demonstrated that excessive mitochondrial fission could lead to the overproduction of reactive oxygen species (ROS) and promote podocyte apoptosis. Therefore, the maintenance of stable mitochondrial function is a newly identified way to protect podocytes and prevent the progression of CKD. As a mitochondria-targeted antioxidant, mitoquinone (MitoQ) has been proven to be a promising agent for the prevention of mitochondrial injury in cardiovascular disease and Parkinson’s disease. The present study examined the effects of MitoQ on angiotensin II- (Ang II-) induced podocyte injury both in vivo and in vitro. Podocyte mitochondria in Ang II-infused mice exhibited morphological and functional alterations. The observed mitochondrial fragmentation and ROS production were alleviated with MitoQ treatment. In vitro, alterations in mitochondrial morphology and function in Ang II-stimulated podocytes, including mitochondrial membrane potential reduction, ROS overproduction, and adenosine triphosphate (ATP) deficiency, were significantly reversed by MitoQ. Moreover, MitoQ rescued the expression and translocation of Nrf2 (nuclear factor E2-related factor 2) and decreased the expression of Keap1 (Kelch-like ECH-associated protein 1) in Ang II-stimulated podocytes. Nrf2 knockdown partially blocked the protective effects of MitoQ on Ang II-induced mitochondrial fission and oxidative stress in podocytes. These results demonstrate that MitoQ exerts a protective effect in Ang II-induced mitochondrial injury in podocytes via the Keap1-Nrf2 signaling pathway.

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Section: Discussionmentioning

confidence: 99%

Mitoquinone Protects Podocytes from Angiotensin II‐Induced Mitochondrial Dysfunction and Injury via the Keap1‐Nrf2 Signaling Pathway

Zhu

Liang

Chen

et al. 2021

Oxidative Medicine and Cellular Longevity

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“…In kidney diseases, the uptake of lipids by CD36, along with the dysfunction of FA β-oxidation, causes lipids accumulation in lipid droplets (LDs), inducing ROS overproduction (Figure 4) [129,130]. Since ROS and their products induce severe cell damage, a cellular balance of ROS is needed.…”

Section: Oxidation and Os Production And In Kidney Diseasesmentioning

confidence: 99%

Mitochondrial Redox Signaling and Oxidative Stress in Kidney Diseases

et al. 2021

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Mitochondria are essential organelles in physiology and kidney diseases, because they produce cellular energy required to perform their function. During mitochondrial metabolism, reactive oxygen species (ROS) are produced. ROS function as secondary messengers, inducing redox-sensitive post-translational modifications (PTM) in proteins and activating or deactivating different cell signaling pathways. However, in kidney diseases, ROS overproduction causes oxidative stress (OS), inducing mitochondrial dysfunction and altering its metabolism and dynamics. The latter processes are closely related to changes in the cell redox-sensitive signaling pathways, causing inflammation and apoptosis cell death. Although mitochondrial metabolism, ROS production, and OS have been studied in kidney diseases, the role of redox signaling pathways in mitochondria has not been addressed. This review focuses on altering the metabolism and dynamics of mitochondria through the dysregulation of redox-sensitive signaling pathways in kidney diseases.

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“…Targeting defective mitochondria‐related pathways has also been proposed as a potential treatment of a variety of diseases, including different types of fibrosis, 26,27 diabetic kidney disease and CKD 28 . Here, using RNA sequencing data from a murine UUO model, 29,30 we identified a pattern of dysregulated genes suggesting an impaired mitochondrial bioenergetics in ligated kidneys following 14 days post‐surgery, compared to non‐ligated kidneys. In general, mitochondria‐related genes were significantly down‐regulated in ligated compared to non‐ligated kidneys.…”

Section: Discussionmentioning

confidence: 94%

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

Hoel

Osman

Hoel

et al. 2021

J Cellular Molecular Medi

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Renal fibrosis is a progressive histological manifestation leading to chronic kidney disease (CKD) and associated with mitochondrial dysfunction. In previous work, we showed that Bemcentinib, an Axl receptor tyrosine kinase inhibitor, reduced fibrosis development. In this study, to investigate its effects on mitochondrial dysfunction in renal fibrosis, we analysed genome‐wide transcriptomics data from a unilateral ureter obstruction (UUO) murine model in the presence or absence of bemcentinib (n = 6 per group) and SHAM‐operated (n = 4) mice. Kidney ligation resulted in dysregulation of mitochondria‐related pathways, with a significant reduction in the expression of oxidative phosphorylation (OXPHOS), fatty acid oxidation (FAO), citric acid cycle (TCA), response to reactive oxygen species and amino acid metabolism‐related genes. Bemcentinib treatment increased the expression of these genes. In contrast, AKT/PI3K signalling pathway genes were up‐regulated upon UUO, but bemcentinib largely inhibited their expression. At the functional level, ligation reduced mitochondrial biomass, which was increased upon bemcentinib treatment. Serum metabolomics analysis also showed a normalizing amino acid profile in UUO, compared with SHAM‐operated mice following bemcentinib treatment. Our data suggest that mitochondria and mitochondria‐related pathways are dramatically affected by UUO surgery and treatment with Axl‐inhibitor bemcentinib partially reverses these effects.

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Mitochondrial dysfunction and endoplasmic reticulum stress in the promotion of fibrosis in obstructive nephropathy induced by unilateral ureteral obstruction

Cited by 46 publications

References 148 publications

Mitoquinone Protects Podocytes from Angiotensin II‐Induced Mitochondrial Dysfunction and Injury via the Keap1‐Nrf2 Signaling Pathway

Mitoquinone Protects Podocytes from Angiotensin II‐Induced Mitochondrial Dysfunction and Injury via the Keap1‐Nrf2 Signaling Pathway

Mitochondrial Redox Signaling and Oxidative Stress in Kidney Diseases

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

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