Mitochondrial dysfunction in kidney injury, inflammation, and disease: Potential therapeutic approaches

Bhatia, Divya; Capili, Allyson; Choi, Mary E.

doi:10.23876/j.krcp.20.082

Cited by 100 publications

(97 citation statements)

References 100 publications

(175 reference statements)

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“…Necroptosis, recently unveiled as a programmed cell death pathway morphologically featuring both necrosis and apoptosis, has been implicated in the development of several diseases [ 25 , 26 ]. Necroptosis is known to play many important roles in the pathway of kidney injury, especially in the setting of acute kidney injury (AKI) [ 27 , 28 ]. Receptor-interacting protein kinase 3 (RIPK3) plays a crucial role in the necroptosis pathway [ 26 ].…”

Section: Introductionmentioning

confidence: 99%

RIPK3 Contributes to Lyso-Gb3-Induced Podocyte Death

Kim

Park

Lee

et al. 2021

Cells

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Fabry disease is a lysosomal storage disease with an X-linked heritage caused by absent or decreased activity of lysosomal enzymes named alpha-galactosidase A (α-gal A). Among the various manifestations of Fabry disease, Fabry nephropathy significantly affects patients’ morbidity and mortality. The cellular mechanisms of kidney damage have not been elusively described. Necroptosis is one of the programmed necrotic cell death pathways and is known to play many important roles in kidney injury. We investigated whether RIPK3, a protein phosphokinase with an important role in necroptosis, played a crucial role in the pathogenesis of Fabry nephropathy both in vitro and in vivo. The cell viability of podocytes decreased after lyso-Gb3 treatment in a dose-dependent manner, with increasing RIPK3 expression. Increased reactive oxygen species (ROS) generation after lyso-Gb3 treatment, which was alleviated by GSK’872 (a RIPK3 inhibitor), suggested a role of oxidative stress via a RIPK3-dependent pathway. Cytoskeleton rearrangement induced by lyso-Gb3 was normalized by the RIPK3 inhibitor. When mice were injected with lyso-Gb3, increased urine albuminuria, decreased podocyte counts in the glomeruli, and effaced foot processes were observed. Our results showed that lyso-Gb3 initiated albuminuria, a clinical manifestation of Fabry nephropathy, by podocyte loss and subsequent foot process effacement. These findings suggest a novel pathway in Fabry nephropathy.

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Section: Introductionmentioning

confidence: 99%

RIPK3 Contributes to Lyso-Gb3-Induced Podocyte Death

Kim

Park

Lee

et al. 2021

Cells

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“…In the present study, the results showed that once ERK activity was inhibited, urinary protein-induced TEC apoptosis and the release of factors that causes renal injury were reduced, suggesting the unfavorable role of ERK pathway in the process. However, the mechanism by which ERK pathway specifically mediates cell injury is currently unclear; it may be related to mitochondrial dysfunction [ 20 , 21 ] or suppression of the Akt pathway which is positive to cell survival [ 22 ]. Notably, ERK inhibitor U0126 failed to completely block urinary protein-induced cell damage, suggesting that a non-ERK pathway may also be involved in mediating the toxicity of urinary proteins.…”

Section: Discussionmentioning

confidence: 99%

ROS-ERK Pathway as Dual Mediators of Cellular Injury and Autophagy-Associated Adaptive Response in Urinary Protein-Irritated Renal Tubular Epithelial Cells

Deng

Zhang

et al. 2021

Journal of Diabetes Research

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ERK, an extracellular signal-regulated protein kinase, is involved in various biological responses, such as cell proliferation and differentiation, cell morphology maintenance, cytoskeletal construction, apoptosis, and canceration of cells. In this study, we focused on ERK pathway on cellular injury and autophagy-associated adaptive response in urinary protein-irritated renal tubular epithelial cells and explored the potential mechanisms underlying it. By using antioxidants N-acetylcysteine and catalase, we found that ERK pathway was activated by a reactive oxygen species- (ROS-) dependent mechanism after exposure to urinary proteins. What is more, ERK inhibitor U0126 could decrease the release of neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), and the number of apoptotic cells induced by urinary proteins, indicating the damaging effects of ERK pathway in mediating cellular injury and apoptosis in HK-2 cells. Interestingly, we also found that the increased expression of microtubule-associated protein 1 light chain 3 (LC3)-II (a key marker of autophagy) and the decreased expression of p62 (autophagic substrate) induced by urinary proteins were reversed by U0126, suggesting autophagy was activated by ERK pathway. Furthermore, rapamycin reduced urinary protein-induced NGAL and KIM-1 secretion and cell growth inhibition, while chloroquine played the opposite effect, indicating that autophagy activation by ERK pathway was an adaptive response in the exposure to urinary proteins. Taken together, our results indicate that activated ROS-ERK pathway can induce cellular injury and in the meantime provide an autophagy-associated adaptive response in urinary protein-irritated renal tubular epithelial cells.

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“…Mechanistically, mitochondrial dysfunction, as discussed above, is an increasingly recognized contributor, particularly in diabetic nephropathy, in which mitochondrial ROS production exceeds the local antioxidant capacity [ 13 , 34 ]. Evidence suggests that mitochondrial dysfunction may also play a role in other kidney diseases, including IgA nephropathy, membranous nephropathy, and polycystic kidney disease [ 35 ]. All of the mechanisms discussed above have been shown to be present in CKD, namely upregulated NOX activity, eNOS uncoupling, and pro-oxidative activities of myeloperoxidase and xanthine oxidase [ 7 , 12 ].…”

Section: Evidence That Oxidative Stress Is Operant In Ckdmentioning

confidence: 99%

Eat Your Broccoli: Oxidative Stress, NRF2, and Sulforaphane in Chronic Kidney Disease

Liebman

2021

Nutrients

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The mainstay of therapy for chronic kidney disease is control of blood pressure and proteinuria through the use of angiotensin-converting enzyme inhibitors (ACE-Is) or angiotensin receptor blockers (ARBs) that were introduced more than 20 years ago. Yet, many chronic kidney disease (CKD) patients still progress to end-stage kidney disease—the ultimate in failed prevention. While increased oxidative stress is a major molecular underpinning of CKD progression, no treatment modality specifically targeting oxidative stress has been established clinically. Here, we review the influence of oxidative stress in CKD, and discuss regarding the role of the Nrf2 pathway in kidney disease from studies using genetic and pharmacologic approaches in animal models and clinical trials. We will then focus on the promising therapeutic potential of sulforaphane, an isothiocyanate derived from cruciferous vegetables that has garnered significant attention over the past decade for its potent Nrf2-activating effect, and implications for precision medicine.

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Mitochondrial dysfunction in kidney injury, inflammation, and disease: Potential therapeutic approaches

Cited by 100 publications

References 100 publications

RIPK3 Contributes to Lyso-Gb3-Induced Podocyte Death

RIPK3 Contributes to Lyso-Gb3-Induced Podocyte Death

ROS-ERK Pathway as Dual Mediators of Cellular Injury and Autophagy-Associated Adaptive Response in Urinary Protein-Irritated Renal Tubular Epithelial Cells

Eat Your Broccoli: Oxidative Stress, NRF2, and Sulforaphane in Chronic Kidney Disease

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