Lipid metabolism in sickness and in health: Emerging regulators of lipotoxicity

Molecular Cell, Journal Year: 2021, Volume and Issue: 81(18), P. 3708 - 3730

Published: Sept. 1, 2021

Language: Английский

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Signaling pathways of chronic kidney diseases, implications for therapeutics

Signal Transduction and Targeted Therapy, Journal Year: 2022, Volume and Issue: 7(1)

Published: June 9, 2022

Abstract Chronic kidney disease (CKD) is a chronic renal dysfunction syndrome that characterized by nephron loss, inflammation, myofibroblasts activation, and extracellular matrix (ECM) deposition. Lipotoxicity oxidative stress are the driving force for loss of including tubules, glomerulus, endothelium. NLRP3 inflammasome signaling, MAPK PI3K/Akt RAAS signaling involves in lipotoxicity. The upregulated Nox expression decreased Nrf2 result directly. injured resident cells release proinflammatory cytokines chemokines to recruit immune such as macrophages from bone marrow. NF-κB JAK-STAT Toll-like receptor cGAS-STING major pathways mediate inflammation inflammatory cells. produce secret great number profibrotic TGF-β1, Wnt ligands, angiotensin II. TGF-β Notch evoke activation promote generation ECM. potential therapies targeted these also introduced here. In this review, we update key lipotoxicity, stress, kidneys with injury, drugs based on latest studies. Unifying will be instrumental advance further basic clinical investigation CKD.

Language: Английский

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Obesity and chronic kidney disease

AJP Endocrinology and Metabolism, Journal Year: 2022, Volume and Issue: 324(1), P. E24 - E41

Published: Nov. 16, 2022

The prevalence of obesity has increased dramatically during the past decades, which been a major health problem. Since 1975, number people with worldwide nearly tripled. An increasing studies find as driver chronic kidney disease (CKD) progression, and mechanisms are complex include hemodynamic changes, inflammation, oxidative stress, activation renin-angiotensin-aldosterone system (RAAS). Obesity-related is characterized by glomerulomegaly, often accompanied localized segmental glomerulosclerosis lesions. In these patients, early symptoms atypical, microproteinuria being main clinical manifestation nephrotic syndrome rare. Weight loss RAAS blockers have protective effect on obesity-related CKD, but even so, significant proportion patients eventually progress to end-stage renal despite treatment. Thus, it critical comprehend underlying CKD create new tactics for slowing or stopping progression. this review, we summarize current knowledge disease, its pathological future perspectives

Language: Английский

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Mechanisms and Models of Kidney Tubular Necrosis and Nephron Loss

Journal of the American Society of Nephrology, Journal Year: 2022, Volume and Issue: 33(3), P. 472 - 486

Published: Jan. 12, 2022

Understanding nephron loss is a primary strategy for preventing CKD progression. Death of renal tubular cells may occur by apoptosis during developmental and regenerative processes. However, AKI, the transition AKI to CKD, sepsis-associated kidney transplantation ferroptosis necroptosis, two pathways associated with plasma membrane integrity, kill cells. This necrotic type cell death an inflammatory response, which referred as necroinflammation. Importantly, necroinflammatory response that die necroptosis be fundamentally different from tissue ferroptosis. Although mechanisms have recently been investigated in detail, propagation necrosis, although described morphologically, remains incompletely understood. Here, we argue molecular switch downstream necrosis determines regeneration versus loss. Unraveling details this "switch" must include signals potentially controlled cells, including stimulation myofibroblasts origin fibrosis. detail responses can inform discussion therapeutic options.

Language: Английский

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Effect of empagliflozin on circulating proteomics in heart failure: mechanistic insights into the EMPEROR programme

European Heart Journal, Journal Year: 2022, Volume and Issue: 43(48), P. 4991 - 5002

Published: Aug. 25, 2022

Abstract Aims Sodium-glucose co-transporter 2 (SGLT2) inhibitors improve cardiovascular outcomes in diverse patient populations, but their mechanism of action requires further study. The aim is to explore the effect empagliflozin on circulating levels intracellular proteins patients with heart failure, using large-scale proteomics. Methods and results Over 1250 were measured at baseline, Week 12, 52 1134 from EMPEROR-Reduced EMPEROR-Preserved, Olink® Explore 1536 platform. Statistical bioinformatical analyses identified differentially expressed (empagliflozin vs. placebo), which then linked demonstrated biological actions kidneys. At 32 1283 fulfilled our threshold for being expressed, i.e. changed by ≥10% a false discovery rate <1% placebo). Among these, nine largest treatment empagliflozin: insulin-like growth factor-binding protein 1, transferrin receptor carbonic anhydrase 2, erythropoietin, protein-glutamine gamma-glutamyltransferase thymosin beta-10, U-type mitochondrial creatine kinase, 4, adipocyte fatty acid-binding 4. changes baseline generally concordant except reduced kidney injury molecule-1 52, not 12. most common appeared be promotion autophagic flux heart, or endothelium, feature 6 proteins. Other effects included reduction oxidative stress, inhibition inflammation fibrosis, enhancement health energy, repair, regenerative capacity. involved autophagy, integrity regeneration, suppression renal modulation tubular sodium reabsorption. Conclusions Changes failure are consistent findings experimental studies that have shown SGLT2 likely related promote flux, nutrient deprivation signalling transmembrane transport.

Language: Английский

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Comprehensive single-cell transcriptional profiling defines shared and unique epithelial injury responses during kidney fibrosis

Cell Metabolism, Journal Year: 2022, Volume and Issue: 34(12), P. 1977 - 1998.e9

Published: Oct. 19, 2022

Language: Английский

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Tubular injury in diabetic kidney disease: molecular mechanisms and potential therapeutic perspectives

Frontiers in Endocrinology, Journal Year: 2023, Volume and Issue: 14

Published: Aug. 2, 2023

Diabetic kidney disease (DKD) is a chronic complication of diabetes and the leading cause end-stage renal (ESRD) worldwide. Currently, there are limited therapeutic drugs available for DKD. While previous research has primarily focused on glomerular injury, recent studies have increasingly emphasized role tubular injury in pathogenesis Various factors, including hyperglycemia, lipid accumulation, oxidative stress, hypoxia, RAAS, ER inflammation, EMT programmed cell death, been shown to induce contribute progression Additionally, traditional hypoglycemic drugs, anti-inflammation therapies, anti-senescence mineralocorticoid receptor antagonists, stem therapies demonstrated their potential alleviate This review will provide insights into latest mechanisms treatments

Language: Английский

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Mitochondrial oxidative damage reprograms lipid metabolism of renal tubular epithelial cells in the diabetic kidney

Cellular and Molecular Life Sciences, Journal Year: 2024, Volume and Issue: 81(1)

Published: Jan. 11, 2024

Abstract The functional and structural changes in the proximal tubule play an important role occurrence development of diabetic kidney disease (DKD). Diabetes-induced metabolic changes, including lipid metabolism reprogramming, are reported to lead state tubular epithelial cells (TECs), among all disturbances metabolism, mitochondria serve as central regulators. Mitochondrial dysfunction, accompanied by increased production mitochondrial reactive oxygen species (mtROS), is considered one primary factors causing injury. Most studies have discussed how altered flux drives oxidative stress during DKD. In present study, we focused on targeting damage upstream factor abnormalities under conditions TECs. Using SS31, a tetrapeptide that protects cristae structure, demonstrated contributes TEC injury peroxidation caused accumulation. Mitochondria protected using SS31 significantly reversed decreased expression key enzymes regulators fatty acid oxidation (FAO), but had no obvious effect major glucose rate-limiting enzymes. facilitated renal Sphingosine-1-phosphate (S1P) deposition limited elevated Acer1, S1pr1 SPHK1 activity, Spns2 expression. These data suggest unbalanced droplet (LD) formulation, peroxidation, impaired FAO sphingolipid homeostasis An vitro study high drove cytosolic phospholipase A2 (cPLA2), which, turn, was responsible for LD generation S1P accumulation, HK-2 cells. A mitochondria-targeted antioxidant inhibited activation cPLA2f isoforms. Taken together, these findings identify mechanistic links between reprogrammed TECs, provide further evidence nephroprotective effects via influencing pathways.

Language: Английский

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Transcriptomic, epigenomic, and spatial metabolomic cell profiling redefines regional human kidney anatomy

Cell Metabolism, Journal Year: 2024, Volume and Issue: 36(5), P. 1105 - 1125.e10

Published: March 20, 2024

A large-scale multimodal atlas that includes major kidney regions is lacking. Here, we employed simultaneous high-throughput single-cell ATAC/RNA sequencing (SHARE-seq) and spatially resolved metabolomics to profile 54 human samples from distinct anatomical regions. We generated transcriptomes of 446,267 cells chromatin accessibility profiles 401,875 developed a package analyze 408,218 metabolomes. find the same cell type, including thin limb, thick ascending limb loop Henle principal cells, display transcriptomic, accessibility, metabolomic signatures, depending on anatomic location. Surveying metabolism-associated gene revealed non-overlapping metabolic signatures between nephron segments dysregulated lipid metabolism in diseased proximal tubule (PT) cells. Integrating omics with clinical data identified PLEKHA1 as disease marker, its vitro knockdown increased expression PT differentiation, suggesting possible pathogenic roles. This study highlights previously underrepresented cellular heterogeneity underlying anatomy.

Language: Английский

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The key role of altered tubule cell lipid metabolism in kidney disease development

Kidney International, Journal Year: 2024, Volume and Issue: 106(1), P. 24 - 34

Published: April 16, 2024

Kidney epithelial cells have very high energy requirements, which are largely met by fatty acid oxidation. Complex changes in lipid metabolism observed patients with kidney disease. Defects oxidation and increased uptake, especially the context of hyperlipidemia proteinuria, contribute to this excess build-up exacerbate disease development. Recent studies also highlighted role de novo lipogenesis fibrosis. The defect causes starvation. Increased synthesis, lower can cause toxic build-up, reactive oxygen species generation, mitochondrial damage. A better understanding these metabolic processes may open new treatment avenues for diseases targeting metabolism.

Language: Английский

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