CPT1α maintains phenotype of tubules via mitochondrial respiration during kidney injury and repair

Qi, Yuan; Lv, Yunhui; Ding, Hao; Ke, Qingqing; Shi, Caifeng; Jiang, Lei; Yang, Junwei; Zhou, Yang

doi:10.1038/s41419-021-04085-w

Cited by 20 publications

(11 citation statements)

References 40 publications

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“…However, E-cadherin was decreased and reached a nadir at day 14 and recovered afterward after folic acid injection. This was similar to the founding of Yuan et al in FA nephropathy [ 48 ]. These factors were considered as the main phase of transdifferentiation.…”

Section: Discussionsupporting

confidence: 92%

IL-18 deficiency ameliorates the progression from AKI to CKD

Luan

Fu²,

Jiao

et al. 2022

Cell Death Dis

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Inflammation is an important factor in the progression from acute kidney injury (AKI) to chronic kidney disease (CKD). The role of interleukin (IL)-18 in this progression has not been examined. We aimed to clarify whether and how IL-18 limits this progression. In a folic acid induced renal injury mouse model, we studied the time course of kidney injury and renal IL-18 expression. In wild-type mice following injection, renal IL-18 expression increased. In parallel, we characterized other processes, including at day 2, renal tubular necroptosis assessed by receptor-interacting serine/threonine-protein kinase1 (RIPK1) and RIPK3; at day 14, transdifferentiation (assessed by transforming growth factor β1, vimentin and E-cadherin); and at day 30, fibrosis (assessed by collagen 1). In IL-18 knockout mice given folate, compared to wild-type mice, tubular damage and necroptosis, transdifferentiation, and renal fibrosis were attenuated. Importantly, IL-18 deletion decreased numbers of renal M1 macrophages and M1 macrophage cytokine levels at day 14, and reduced M2 macrophages numbers and macrophage cytokine expression at day 30. In HK-2 cells, IL-18 knockdown attenuated necroptosis, transdifferentiating and fibrosis.In patients with tubulointerstitial nephritis, IL-18 protein expression was increased on renal biopsies using immunohistochemistry. We conclude that genetic IL-18 deficiency ameliorates renal tubular damage, necroptosis, cell transdifferentiation, and fibrosis. The renoprotective role of IL-18 deletion in the progression from AKI to fibrosis may be mediated by reducing a switch in predominance from M1 to profibrotic M2 macrophages during the process of kidney repair.

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Section: Discussionsupporting

confidence: 92%

IL-18 deficiency ameliorates the progression from AKI to CKD

Luan

Fu²,

Jiao

et al. 2022

Cell Death Dis

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“…Transcription of CPT1, which is required for fatty acid transport into the mitochondria, was significantly higher in rAZGP1 treated mice, whereas it was reduced in AZGP1 deficient kidneys. Yuan et al recently demonstrated that genetic ablation of CPT1 aggravated tubular injury and promoted interstitial fibrosis [ 25 ]. Accordingly, Miguel et al found that the development of kidney fibrosis could be efficiently rescued by overexpressing CPT1 in tubular cells [ 23 ].…”

Section: Discussionmentioning

confidence: 99%

The Therapeutic Potential of Zinc-Alpha2-Glycoprotein (AZGP1) in Fibrotic Kidney Disease

Sörensen-Zender

Rong

Haller

et al. 2022

IJMS

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Chronic kidney disease (CKD) is characterized by a long-term loss of kidney function and, in most cases, by progressive fibrosis. Zinc-alpha2-glycoprotein (AZGP1) is a secreted protein, which is expressed in many different tissues and has been associated with a variety of functions. In a previous study, we have shown in cell culture and in AZGP1 deficient mice that AZGP1 has protective anti-fibrotic effects. In the present study, we tested the therapeutic potential of an experimental increase in AZGP1 using two different strategies. (1) C57Bl/6J mice were treated systemically with recombinant AZGP1, and (2) a transgenic mouse strain was generated to overexpress AZGP1 conditionally in proximal tubular cells. Mice underwent unilateral uretic obstruction as a pro-fibrotic kidney stress model, and kidneys were examined after 14 days. Recombinant AZGP1 treatment was accompanied by better preservation of tubular integrity, reduced collagen deposition, and lower expression of injury and fibrosis markers. Weaker but similar tendencies were observed in transgenic AZGP1 overexpressing mice. Higher AZGP1 levels led to a significant reduction in stress-induced accumulation of tubular lipid droplets, which was paralleled by improved expression of key players in lipid metabolism and fatty acid oxidation. Together these data show beneficial effects of elevated AZGP1 levels in fibrotic kidney disease and highlight a novel link to tubular cell lipid metabolism, which might open up new opportunities for CKD treatment.

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“…During cuproptosis, copper ions directly bind to lipid-acylated components of the tricarboxylic acid cycle pathway, leading to abnormal aggregation of lipid-acylated proteins and loss of iron-sulfur cluster proteins and resulting in a proteotoxic stress response that leads to cell death ( 5 ). Kidney disease is closely linked to mitochondrial dysfunction ( 28 – 30 ), and inhibition of mitochondrial respiration significantly enhances the efficacy of chemotherapy for renal cell carcinoma ( 31 ). The use of copper ion carriers to kill cancer cells is a potential new treatment for cancer.…”

Section: Discussionmentioning

confidence: 99%

Molecular Subtyping Based on Cuproptosis-Related Genes and Characterization of Tumor Microenvironment Infiltration in Kidney Renal Clear Cell Carcinoma

Ren

Wang

et al. 2022

Front. Oncol.

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The incidence of kidney renal clear cell carcinoma (KIRC) is rising worldwide, and the prognosis is poor. Cuproptosis is a new form of cell death that is dependent on and regulated by copper ions. The relationship between cuproptosis and KIRC remains unclear. In the current study, changes in cuproptosis-related genes (CRGs) in TCGA-KIRC transcriptional datasets were characterized, and the expression patterns of these genes were analyzed. We identified three main molecular subtypes and discovered that multilayer CRG changes were associated with patient clinicopathological traits, prognosis, elesclomol sensitivity, and tumor microenvironment (TME) cell infiltration characteristics. Then, a CRG score was created to predict overall survival (OS). The CRG score was found to be strongly linked to the TME. These findings may help elucidate the roles of CRGs in KIRC, potentially enhancing understanding of cuproptosis and supporting the development of more effective immunotherapy strategies.

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CPT1α maintains phenotype of tubules via mitochondrial respiration during kidney injury and repair

Cited by 20 publications

References 40 publications

IL-18 deficiency ameliorates the progression from AKI to CKD

IL-18 deficiency ameliorates the progression from AKI to CKD

The Therapeutic Potential of Zinc-Alpha2-Glycoprotein (AZGP1) in Fibrotic Kidney Disease

Molecular Subtyping Based on Cuproptosis-Related Genes and Characterization of Tumor Microenvironment Infiltration in Kidney Renal Clear Cell Carcinoma

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