Mitochondrial dysfunction and the AKI-to-CKD transition

Jiang, Meiyan; Bai, Mei; Lei, Juan; Xie, Yifan; Xu, Shuang; Jia, Zhanjun; Zhang, Aihua

doi:10.1152/ajprenal.00285.2020

Cited by 122 publications

(85 citation statements)

References 132 publications

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“…Pathogenesis of CKD was confirmed by observing increased fibrosis region and glomerulus size in H&E staining (Figure 1A). Many have reported on the role of dysregulated mitochondrial dynamics in CKD [7,19,20], and this was consistent with our TEM data showing abnormal mitochondrial morphology (Figure 1B). In addition to commonly reported mitochondrial fragmentation, we observed abnormally elongated mitochondria and an increase in both mitochondrial area and percentage of abnormal mitochondria (Figure 1C,D).…”

Section: The Kidney Of Ckd Mice Has Dysregulated Mitochondrial Dynamics and Mitophagysupporting

confidence: 93%

Melatonin Treatment Improves Renal Fibrosis via miR-4516/SIAH3/PINK1 Axis

Yoon

Yoon³

et al. 2021

Cells

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Dysregulation in mitophagy, in addition to contributing to imbalance in the mitochondrial dynamic, has been implicated in the development of renal fibrosis and progression of chronic kidney disease (CKD). However, the current understanding of the precise mechanisms behind the pathogenic loss of mitophagy remains unclear for developing cures for CKD. We found that miR-4516 is downregulated and its target SIAH3, an E3 ubiquitin protein ligase that reduces PINK1 accumulation to damaged mitochondria, is upregulated in the renal cortex of CKD mice. Here, we demonstrated that melatonin injection induces miR-4516 expression and suppresses SIAH3, and promotes PINK1/Parkin-mediated mitophagy. Furthermore, we demonstrated that melatonin injection attenuates the pathological features of CKD by improving mitochondrial homeostasis. Our data supports that mitochondrial autophagy regulation by activating miR-4516/SIAH3/PINK1 mitophagy signaling axis can be a viable new strategy for treating CKD.

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Section: The Kidney Of Ckd Mice Has Dysregulated Mitochondrial Dynamics and Mitophagysupporting

confidence: 93%

Melatonin Treatment Improves Renal Fibrosis via miR-4516/SIAH3/PINK1 Axis

Yoon

Yoon³

et al. 2021

Cells

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“…Mitochondria are very sensitive to changes in environmental factors, which may cause mitochondrial dysfunction [ 39 ]. Mitochondrial dysfunction may result in a decrease of ATP generation, an increase of reactive oxygen species level and an induction of apoptosis, all of which contribute to the development and progression of AKI and CKD as well as AKI to CKD transition.…”

Section: The Roles Of Mitochondrial In Aki Ckd and Aki To Ckd Transitionmentioning

confidence: 99%

The Role of Mitochondria in Acute Kidney Injury and Chronic Kidney Disease and Its Therapeutic Potential

Zhang

Agborbesong

2021

IJMS

107

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Mitochondria are heterogeneous and highly dynamic organelles, playing critical roles in adenosine triphosphate (ATP) synthesis, metabolic modulation, reactive oxygen species (ROS) generation, and cell differentiation and death. Mitochondrial dysfunction has been recognized as a contributor in many diseases. The kidney is an organ enriched in mitochondria and with high energy demand in the human body. Recent studies have been focusing on how mitochondrial dysfunction contributes to the pathogenesis of different forms of kidney diseases, including acute kidney injury (AKI) and chronic kidney disease (CKD). AKI has been linked to an increased risk of developing CKD. AKI and CKD have a broad clinical syndrome and a substantial impact on morbidity and mortality, encompassing various etiologies and representing important challenges for global public health. Renal mitochondrial disorders are a common feature of diverse forms of AKI and CKD, which result from defects in mitochondrial structure, dynamics, and biogenesis as well as crosstalk of mitochondria with other organelles. Persistent dysregulation of mitochondrial homeostasis in AKI and CKD affects diverse cellular pathways, leading to an increase in renal microvascular loss, oxidative stress, apoptosis, and eventually renal failure. It is important to understand the cellular and molecular events that govern mitochondria functions and pathophysiology in AKI and CKD, which should facilitate the development of novel therapeutic strategies. This review provides an overview of the molecular insights of the mitochondria and the specific pathogenic mechanisms of mitochondrial dysfunction in the progression of AKI, CKD, and AKI to CKD transition. We also discuss the possible beneficial effects of mitochondrial-targeted therapeutic agents for the treatment of mitochondrial dysfunction-mediated AKI and CKD, which may translate into therapeutic options to ameliorate renal injury and delay the progression of these kidney diseases.

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“…Regarding the kidney, accumulation of senescent (in particular tubular epithelial) cells has been implicated in regeneration failure and AKI-to-CKD transition ( Schmitt and Cantley, 2008 ; O’Sullivan et al, 2017 ; Kim et al, 2019 ). In this sense, prolonged tubular epithelial cell-cycle arrest, sustained inflammation, and impaired mitochondrial function can contribute to CKD progression ( Levey and James, 2017 ; Andrade et al, 2018 ; Sato and Yanagita, 2018 ; Jiang et al, 2020 ). Cellular senescence or premature aging in the kidney is characterized by increased expression of some cell-cycle-related molecules such as the cyclin kinase inhibitors p16ink4a, p21cip, and p53 ( Melk et al, 2004 ; Andrade et al, 2018 ; Knoppert et al, 2019 ; Koyano et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

Acute Kidney Injury is Aggravated in Aged Mice by the Exacerbation of Proinflammatory Processes

et al. 2021

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Acute kidney injury (AKI) is more frequent in elderly patients. Mechanisms contributing to AKI (tubular cell death, inflammatory cell infiltration, impaired mitochondrial function, and prolonged cell-cycle arrest) have been linked to cellular senescence, a process implicated in regeneration failure and progression to fibrosis. However, the molecular and pathological basis of the age-related increase in AKI incidence is not completely understood. To explore these mechanisms, experimental AKI was induced by folic acid (FA) administration in young (3-months-old) and old (1-year-old) mice, and kidneys were evaluated in the early phase of AKI, at 48 h. Tubular damage score, KIM-1 expression, the recruitment of infiltrating immune cells (mainly neutrophils and macrophages) and proinflammatory gene expression were higher in AKI kidneys of old than of young mice. Tubular cell death in FA-AKI involves several pathways, such as regulated necrosis and apoptosis. Ferroptosis and necroptosis cell-death pathways were upregulated in old AKI kidneys. In contrast, caspase-3 activation was only found in young but not in old mice. Moreover, the antiapoptotic factor BCL-xL was significantly overexpressed in old, injured kidneys, suggesting an age-related apoptosis suppression. AKI kidneys displayed evidence of cellular senescence, such as increased levels of cyclin dependent kinase inhibitors p16ink4a and p21cip1, and of the DNA damage response marker γH2AX. Furthermore, p21cip1 mRNA expression and nuclear staining for p21cip1 and γH2AX were higher in old than in young FA-AKI mice, as well as the expression of senescence-associated secretory phenotype (SASP) components (Il-6, Tgfb1, Ctgf, and Serpine1). Interestingly, some infiltrating immune cells were p21 or γH2AX positive, suggesting that molecular senescence in the immune cells (“immunosenescence”) are involved in the increased severity of AKI in old mice. In contrast, expression of renal protective factors was dramatically downregulated in old AKI mice, including the antiaging factor Klotho and the mitochondrial biogenesis driver PGC-1α. In conclusion, aging resulted in more severe AKI after the exposure to toxic compounds. This increased toxicity may be related to magnification of proinflammatory-related pathways in older mice, including a switch to a proinflammatory cell death (necroptosis) instead of apoptosis, and overactivation of cellular senescence of resident renal cells and infiltrating inflammatory cells.

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Mitochondrial dysfunction and the AKI-to-CKD transition

Cited by 122 publications

References 132 publications

Melatonin Treatment Improves Renal Fibrosis via miR-4516/SIAH3/PINK1 Axis

Melatonin Treatment Improves Renal Fibrosis via miR-4516/SIAH3/PINK1 Axis

The Role of Mitochondria in Acute Kidney Injury and Chronic Kidney Disease and Its Therapeutic Potential

Acute Kidney Injury is Aggravated in Aged Mice by the Exacerbation of Proinflammatory Processes

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