The role of lipotoxicity in kidney disease: From molecular mechanisms to therapeutic prospects

Ren, Luping; Cui, Haiying; Wang, Yao; Feng, Jianhua; Cai, Yunjia; Gang, Xiaokun; Wang, Guixia

doi:10.1016/j.biopha.2023.114465

Cited by 14 publications

(6 citation statements)

References 165 publications

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“…Additionally, TPS3A significantly reduced the HFD-induced elevation of renal triglyceride and cholesterol levels, providing additional favorable evidence of its beneficial effects on ameliorating renal tubular ELD (Figure F). Long-term exposure to an overload of lipids could compromise the antioxidant defenses of cells and lead to aberrant expression of inflammation-related cytokines, which is a common pathological manifestation of ELD-induced lipotoxic injury in renal tubular cells . As illustrated in Figure G, compared to the ND group, there was a considerable upregulation of renal proinflammatory cytokines: tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), and monocyte chemoattractant protein-1 (MCP-1) levels, and a notable downregulation of renal anti-inflammatory cytokines: interleukin-10 (IL-10), interleukin-4 (IL-4), interleukin-13 (IL-13), and interleukin-22 (IL-22) levels, in HFD-exposed mice, whereas TPS3A administration significantly altered the inflammatory cytokine profile.…”

Section: Resultsmentioning

confidence: 99%

Tea Polysaccharide Ameliorates High-Fat Diet-Induced Renal Tubular Ectopic Lipid Deposition via Regulating the Dynamic Balance of Lipogenesis and Lipolysis

Kuang,

Li,

Qian

et al. 2024

J. Agric. Food Chem.

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Renal tubular ectopic lipid deposition (ELD) plays a significant role in the development of chronic kidney disease, posing a great threat to human health. The present work aimed to explore the intervention effect and potential molecular mechanism of a purified tea polysaccharide (TPS3A) on renal tubular ELD. The results demonstrated that TPS3A effectively improved kidney function and slowed the progression of tubulointerstitial fibrosis in high-fat-diet (HFD)-exposed ApoE −/− mice. Additionally, TPS3A notably suppressed lipogenesis and enhanced lipolysis, as shown by the downregulation of lipogenesis markers (SREBP-1 and FAS) and the upregulation of lipolysis markers (HSL and ATGL), thereby reducing renal tubular ELD in HFD-fed ApoE −/− mice and palmitic-acid-stimulated HK-2 cells. The AMPK-SIRT1-FoxO1 axis is a core signal pathway in regulating lipid deposition. Consistently, TPS3A significantly increased the levels of phosphorylated-AMPK, SIRT1, and deacetylation of Ac-FoxO1. However, these effects of TPS3A on lipogenesis and lipolysis were abolished by AMPK siRNA, SIRT1 siRNA, and FoxO1 inhibitor, resulting in exacerbated lipid deposition. Taken together, TPS3A shows promise in ameliorating renal tubular ELD by inhibiting lipogenesis and promoting lipolysis through the AMPK-SIRT1-FoxO1 signaling pathway.

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Section: Resultsmentioning

confidence: 99%

Tea Polysaccharide Ameliorates High-Fat Diet-Induced Renal Tubular Ectopic Lipid Deposition via Regulating the Dynamic Balance of Lipogenesis and Lipolysis

Kuang,

Li,

Qian

et al. 2024

J. Agric. Food Chem.

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“…Lipotoxicity in renal TECs is associated with inflammation, oxidative stress, mitochondrial dysfunction and cell death ( 27 ). Fatty acid overload in mitochondria causes incomplete β-oxidation, which increases oxidative stress, induces mitochondrial dysfunction, and promotes ROS production.…”

Section: Mechanismmentioning

confidence: 99%

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

et al. 2023

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

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“…ER stress and mitochondrial dysfunction are well-recognized contributors to the onset of oxidative stress [58,59]. Interestingly, both are the important mechanisms of lipidinduced toxicity [60]. In fact, lipotoxicity has been found to induce apoptosis in mesangial cells through the activation of the protein kinase RNA-like endoplasmic reticulum kinase (PERK) and activating transcription factor 6 (ATF6) signaling pathways, which was diminished via a PRMT1 knock down.…”

Section: Lipid-induced Oxidative Stress In Lipid-rich Kidney Disease ...mentioning

confidence: 99%

Oxidative Stress Induced by Lipotoxicity and Renal Hypoxia in Diabetic Kidney Disease and Possible Therapeutic Interventions: Targeting the Lipid Metabolism and Hypoxia

Chae,

Kim,

Park

2023

Antioxidants

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Oxidative stress, a hallmark pathophysiological feature in diabetic kidney disease (DKD), arises from the intricate interplay between pro-oxidants and anti-oxidants. While hyperglycemia has been well established as a key contributor, lipotoxicity emerges as a significant instigator of oxidative stress. Lipotoxicity encompasses the accumulation of lipid intermediates, culminating in cellular dysfunction and cell death. However, the mechanisms underlying lipotoxic kidney injury in DKD still require further investigation. The key role of cell metabolism in the maintenance of cell viability and integrity in the kidney is of paramount importance to maintain proper renal function. Recently, dysfunction in energy metabolism, resulting from an imbalance in oxygen levels in the diabetic condition, may be the primary pathophysiologic pathway driving DKD. Therefore, we aim to shed light on the pivotal role of oxidative stress related to lipotoxicity and renal hypoxia in the initiation and progression of DKD. Multifaceted mechanisms underlying lipotoxicity, including oxidative stress with mitochondrial dysfunction, endoplasmic reticulum stress activated by the unfolded protein response pathway, pro-inflammation, and impaired autophagy, are delineated here. Also, we explore potential therapeutic interventions for DKD, targeting lipotoxicity- and hypoxia-induced oxidative stress. These interventions focus on ameliorating the molecular pathways of lipid accumulation within the kidney and enhancing renal metabolism in the face of lipid overload or ameliorating subsequent oxidative stress. This review highlights the significance of lipotoxicity, renal hypoxia-induced oxidative stress, and its potential for therapeutic intervention in DKD.

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The role of lipotoxicity in kidney disease: From molecular mechanisms to therapeutic prospects

Cited by 14 publications

References 165 publications

Tea Polysaccharide Ameliorates High-Fat Diet-Induced Renal Tubular Ectopic Lipid Deposition via Regulating the Dynamic Balance of Lipogenesis and Lipolysis

Tea Polysaccharide Ameliorates High-Fat Diet-Induced Renal Tubular Ectopic Lipid Deposition via Regulating the Dynamic Balance of Lipogenesis and Lipolysis

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

Oxidative Stress Induced by Lipotoxicity and Renal Hypoxia in Diabetic Kidney Disease and Possible Therapeutic Interventions: Targeting the Lipid Metabolism and Hypoxia

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