m6A eraser FTO modulates autophagy by targeting SQSTM1/P62 in the prevention of canagliflozin against renal fibrosis

Frontiers in Immunology, Journal Year: 2023, Volume and Issue: 13

Published: Jan. 4, 2023

The dysregulation of autophagy contributes to renal fibrosis. N6-Methyladenosine (m6A) RNA modification is a critical mediator autophagy. Our previous studies have reported that the disorder PPARα/fatty acid oxidation (FAO) axis in tubular cells suppressed by STAT6, which involved regulation fibrotic processes. Here, we found canagliflozin significantly upregulates SQSTM1/P62, promoting PPARα-mediated FAO inducing autophagy-dependent STAT6 degradation both TGF-β1-treated HK2 and unilateral ureteral occlusion (UUO) ischemia–reperfusion (I/R) fibrosis mouse models. Knockdown P62/SQSTM1 led impairment autophagic flux STAT6/PPARα axis, was confirmed SQSTM1/P62 cKO mice with UUO treatment along bioinformatics analysis. Furthermore, deficiency inhibited canagliflozin’s effects prevent Mechanistically, level m6A eraser FTO, interacted SQSTM1 mRNA, decreased vitro vivo after administration. Decrease FTO stabilized induced autophagosome formation. Collectively, this study uncovered previously unrecognized function modulation through mRNA stability STAT6/PPARα/FAO

Language: Английский

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Aldehyde dehydrogenase 2 alleviates mitochondrial dysfunction by promoting PGC-1α-mediated biogenesis in acute kidney injury

Cell Death and Disease, Journal Year: 2023, Volume and Issue: 14(1)

Published: Jan. 20, 2023

Renal tubular epithelial cells are one of the high energy-consuming cell types, which mainly depend on mitochondrial energy supply. Aldehyde dehydrogenase 2 (ALDH2) is a key enzyme that involved in alcohol metabolism and oxidative ATP production; however, its function homoeostasis acute kidney injury (AKI) unclear. Here, we found ALDH2 expression was predominantly decreased cisplatin or maleic acid (MA) models both vivo vitro. knockout (KO) mice exhibited exacerbated impairment apoptosis after injection. In contrast, activation alleviated AKI cisplatin- MA-induced models. RNA sequencing revealed phosphorylation pathway positively enriched renal tissues Alda-1 pre-treatment mice. restored structure, membrane potential, respiration rate, but downregulated glycolysis human proximal (HK-2) cells. Mechanistically, co-immunoprecipitation assays interacts with peroxisomal proliferator-γ coactivator-1α (PGC-1α), master regulator biogenesis, advanced nuclear translocation. Subsequently, PGC-1α knockdown almost abolished improvement damage. Thus, our study dysfunction by enhancing PGC-1α-mediated biogenesis. Hence, may act as potential therapeutic target to prevent progression.

Language: Английский

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Aldehyde dehydrogenase 2 protects against acute kidney injury by regulating autophagy via Beclin-1 pathway

JCI Insight, Journal Year: 2021, Volume and Issue: unknown

Published: July 6, 2021

The mitochondrial enzyme aldehyde dehydrogenase 2 (ALDH2) catalyzes the detoxification of acetaldehyde and endogenous lipid aldehydes. Approximately 40% East Asians, accounting for 8% human population, carry E504K mutation in ALDH2 that leads to accumulation toxic reactive aldehydes increases risk cardiovascular disease, cancer, Alzheimer among others. However, role acute kidney injury (AKI) remains poorly defined is therefore subject present study using various cellular organismal sources. In murine models, which AKI was induced by either contrast agent iohexol or renal ischemia/reperfusion, KO, activation/overexpression were associated with increased decreased injury, respectively. tubular epithelial cells (RTECs), upregulated Beclin-1 expression, promoted autophagy activation, eliminated ROS. vivo vitro, both 3-MA siRNAs inhibited abolished ALDH2-mediated renoprotection. mice iohexol-induced AKI, knockdown RTECs AAV-shRNA impaired activation aggravated injury. proximal HK-2 exposed iohexol, potentiated attenuated apoptosis. overexpression pretreatment regulated mitigating apoptosis summary, our data collectively substantiate a critical via involving pathway.

Language: Английский

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Influence of NF-κB on the development of oxidative-nitrosative stress in the liver of rats under conditions of chronic alcohol intoxication

The Ukrainian Biochemical Journal, Journal Year: 2023, Volume and Issue: 94(6), P. 57 - 66

Published: Feb. 23, 2023

Alcohol-related liver disease is the most common cause of worldwide. The purpose this work establishment influence transcription factor κB on development oxidative-nitrosative stress in rats under conditions chronic alcohol intoxication. experiments were performed 24 male Wistar weighing 180-220 g. animals divided into 4 groups 6 animals: control; animals, which administered NF-κB inhibitor, namely ammonium pyrrolidinedithio­carbamate (PDTC) at a dose 76 mg/kg 3 times week; we simulated alcoholic hepatitis and group combination inhibitor. We determined rat homogenate following biochemical parameters: activi­ty NO synthase isoforms, superoxide dismutase catalase activity, concentration malonic dialdehyde, peroxynitrite, nitrites nitrosothiols, sulfide anion radical production. Chronic intoxication led to increased production reactive oxygen nitrogen species background decreased antioxidant thus intensifying lipid peroxidation liver. Blockade during despite an increase activity decrease did not ameliorate oxidative damage activation nuclear by PDTC reduced risk hepatocytes, but reduce developing nitrosative hepatocytes. Keywords: intoxication, NF-κB, stress, PDTC,

Language: Английский

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Acute high‐altitude hypoxia exposure causes neurological deficits via formaldehyde accumulation

CNS Neuroscience & Therapeutics, Journal Year: 2022, Volume and Issue: 28(8), P. 1183 - 1194

Published: May 18, 2022

Abstract Introduction Acute high‐altitude hypoxia exposure causes multiple adverse neurological consequences. However, the exact mechanisms are still unclear, and there is no targeted treatment with few side effects. Excessive cerebral formaldehyde (FA) impairs numerous functions, can be eliminated by nano‐packed coenzyme Q10 (CoQ10). Aims In this study, we aimed to investigate whether FA was accumulated after hypobaric exposure, further explored preventative effect of CoQ10 through elimination. Results Accumulated found in C57BL/6 mice acute which resulted metabolic disturbance elevation semicarbazide‐sensitive amine oxidase, declination aldehyde dehydrogenase‐2. also induce neuronal ferroptosis vivo. Excitingly, administration for 3 days before reduced accumulation, alleviated subsequent ferroptosis, preserved functions. Conclusion Cerebral accumulation mediates deficits under hypoxia, supplementation may a promising strategy visitors sojourners at plateau.

Language: Английский

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Autophagy in acute kidney injury and maladaptive kidney repair

Burns & Trauma, Journal Year: 2023, Volume and Issue: 11

Published: Jan. 1, 2023

Abstract Acute kidney injury (AKI) is a major renal disease characterized by sudden decrease in function. After AKI, the has ability to repair, but if initial severe repair may be incomplete or maladaptive and result chronic problems. Autophagy highly conserved pathway deliver intracellular contents lysosomes for degradation. plays an important role maintaining function involved pathogenesis of diseases. activated various forms AKI acts as defense mechanism against cell death. autophagy maintained at relatively high level tubule cells during been controversial. Nonetheless, recent studies have demonstrated that contribute after inducing tubular degeneration promoting profibrotic phenotype cells. In this review, we analyze regulation discuss therapeutic strategies targeting autophagy.

Language: Английский

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From Rare Disorders of Kidney Tubules to Acute Renal Injury: Progress and Prospective

Kidney Diseases, Journal Year: 2024, Volume and Issue: 10(2), P. 153 - 166

Published: Jan. 1, 2024

<b><i>Background:</i></b> Acute kidney injury (AKI) is a severe condition marked by rapid renal function deterioration and elevated mortality, with traditional biomarkers lacking sensitivity specificity. Rare tubulointerstitial diseases encompass spectrum of disorders, primarily including monogenic diseases, immune-related conditions, drug-induced diseases. The clinical manifestations vary from electrolyte acid-base imbalances to insufficiency, which associated AKI in up 20% cases. Evidence indicated that rare might provide new conceptual insights perspectives for novel potential therapeutic strategies AKI. <b><i>Summary:</i></b> Autosomal dominant disease (ADTKD) Fanconi syndrome (FS) are In ADTKD, UMOD REN closely related affecting oxidative stress tubuloglomerular feedback, Both share etiologies treatment responses. From the mechanism standpoint, involve tubular transporter injury, initially manifesting as dysfunction disorder progressing because programmed cell death apoptosis, pyroptosis, or necroptosis proximal tubule cells. Additionally, mitochondrial has been identified common both induced drugs, pSS, monoclonal end, FS patients animal models responded well therapy primary <b><i>Key Messages:</i></b> this review, we describe an overview ADTKD identify their associations Mitochondrial contributes AKI, target.

Language: Английский

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Aldehyde Dehydrogenase 2 Ameliorates LPS-Induced Acute Kidney Injury through Detoxification of 4-HNE and Suppression of the MAPK Pathway

Journal of Immunology Research, Journal Year: 2023, Volume and Issue: 2023, P. 1 - 12

Published: April 6, 2023

Lipopolysaccharide (LPS)-induced septic acute kidney injury (AKI) is determined as a devastating organ dysfunction elicited by an inappropriate response to infection with high morbidity and mortality rates. Previous evidence has illustrated indispensable role of mitochondrial aldehyde dehydrogenase 2 (ALDH2) in the pathogenesis sepsis-induced multiorgan abnormalities. Specifically, this study investigated potential ALDH2 AKI. After LPS administration, we observed significant decline renal function, increased inflammatory cytokines, oxidative stress, 4-hydroxy-2-nonenal (4-HNE) accumulation, apoptosis via MAPK activation ALDH2−/− mice; contrast, pretreatment Alda-1 (an activator) alleviated LPS-induced dysfunctions mice. Moreover, vitro analysis revealed that overexpression mouse tubular epithelial cells (mTECs) improved response, 4-HNE inhibition, whereas knockdown mTECs aggravated these parameters activation. Therefore, may protect against AKI suppressing 4-HNE/MAPK pathway.

Language: Английский

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Twist2 knockdown alleviates renal ischemia–reperfusion injury by maintaining mitochondrial function and enhancing mitophagy through Bnip3

Human Cell, Journal Year: 2025, Volume and Issue: 38(2)

Published: Feb. 7, 2025

Language: Английский

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Identification of ALDH2 as a novel target for the treatment of acute kidney injury in kidney transplantation based on WGCNA and machine learning algorithms and exploration of its potential mechanism of action using animal experiments

Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 16

Published: March 4, 2025

Background Acute kidney injury (AKI) after transplantation is one of the main causes graft loss and poor patient prognosis, it important to explore new targets for treating AKI in transplantation. Methods Based on AKI-related dataset GSE30718, most relevant modular genes among them were firstly screened using WGCNA intersected with DEGs, used as candidate AKI. Second, machine learning algorithms utilized identify key them, HPA database was expression landscape. Next, we constructed a rat renal IRI model explored role IRI. Finally, combined ssGSEA enrichment analysis animal experiments further validate potential mechanism action genes. Results In total, identified 98 417 which yield total 24 by three types learning, namely, Random Forest, LASSO regression SVM, obtained 1 gene ALDH2, Using database, found that ALDH2 has high level tissues mainly located tubular epithelial cells. increasing alleviated impairment function decreased NGAL, marker injury, BAX, an apoptotic protein, well reducing inflammatory factors IL1β IL6. experiments, able inhibit activation MAPK signaling pathway. Conclusion may serve novel target treatment AKI, protective effect IRI, this be achieved inhibiting

Language: Английский

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