Kruppel‐like factor 4 improves obesity‐related nephropathy through increasing mitochondrial biogenesis and activities

Jin, Lingwei; Ye, Hanyang; Pan, Min; Chen, Yan; Ye, Bairu; Zheng, Yu; Huang, Wenwen; Pan, Shufang; Zhang, Jing

doi:10.1111/jcmm.14628

Cited by 6 publications

(2 citation statements)

References 33 publications

(152 reference statements)

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“…TLRs have been regarded as sensors that mediate inflammation by identifying pathogens and activating downstream signaling pathways that lead to the upregulation of inflammatory gene expression ( 31 ). Conversely, the activation of KLF4 serves a protective role in the inflammatory response ( 32 ). The activation of the TLR4-mediated inflammatory pathway in the saturated fatty acid response has been confirmed in different types of cells ( 33-35 ).…”

Section: Discussionmentioning

confidence: 99%

Palmitic acid up regulates Gal‑3 and induces insulin resistance in macrophages by mediating the balance between KLF4 and NF‑κB

et al. 2021

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Insulin resistance is the main sign of type 2 diabetes mellitus and is often accompanied by the infiltration of inflammatory factors. These inflammatory factors are mainly produced and secreted by macrophages. The purpose of the current study was to explore the relationship between macrophages and insulin resistance, and to determine its underlying mechanism. The insulin resistance of macrophages was induced by palmitic acid (PA) in vitro. The glucose uptake rate of macrophages, the expression levels of inflammatory cytokines and the expression levels of insulin resistance-related proteins were detected. The protein expression levels of Krüppel-like factor 4 (KLF4), toll-like receptor 4 (TLR4), NF-κB and Galectin-3 (Gal-3) were detected via western blotting and recovery experiments were performed by combining the Gal-3 and TLR4 inhibitors GB1107 and TAK242. The results revealed that PA-induced macrophages demonstrated insulin resistance. Additionally, KLF4 protein was inhibited and the sugar uptake rate was significantly lower than that of the control group. Western blotting and immunofluorescence assays revealed that the expression of Gal-3 in PA-induced macrophages was significantly upregulated. The addition of the Gal-3 inhibitor GB1107 significantly increased glucose utilization and reduced insulin resistance in PA-treated cells. Inhibitor of TLR4 inhibited the protein expression level of the TLR4/NF-κB pathway. In conclusion, PA promoted the TLR4/phosphorylated-NF-κB signaling pathway by inhibiting KLF4, promoted the upregulation of Gal-3 expression and improved the insulin resistance of macrophages.

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Section: Discussionmentioning

confidence: 99%

Palmitic acid up regulates Gal‑3 and induces insulin resistance in macrophages by mediating the balance between KLF4 and NF‑κB

et al. 2021

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“…However, in kidney injury, fatty acid utilization is disrupted, leading to lipid accumulation and subsequent lipotoxicity damages, characterized by mitochondrial impairment, endoplasmic reticulum stress, and increased reactive oxygen species production, etc. 19 - 22 . Numerous studies have confirmed that lipotoxicity plays a key role in renal fibrosis 23 - 25 .…”

Section: Introductionmentioning

confidence: 99%

MAGL protects against renal fibrosis through inhibiting tubular cell lipotoxicity

Zhou,

Ling,

Zhu

et al. 2024

Theranostics

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Rationale: Renal fibrosis, with no therapeutic approaches, is a common pathological feature in various chronic kidney diseases (CKD). Tubular cell injury plays a pivotal role in renal fibrosis. Commonly, injured tubular cells exhibit significant lipid accumulation. However, the underlying mechanisms remain poorly understood. Methods: 2-arachidonoylglycerol (2-AG) levels in CKD patients and CKD model specimens were measured using mass spectrometry. 2-AG-loaded nanoparticles were infused into unilateral ureteral obstruction (UUO) mice. Lipid accumulation and renal fibrosis were tested. Furthermore, monoacylglycerol lipase (MAGL), the hydrolyzing enzyme of 2-AG, was assessed in CKD patients and models. Tubular cell-specific MAGL knock-in mice were generated. Moreover, MAGL recombination protein was also administered to unilateral ischemia reperfusion injury (UIRI) mice. Besides, a series of methods including RNA sequencing, metabolomics, primary cell culture, lipid staining, etc. were used. Results: 2-AG was increased in the serum or kidneys from CKD patients and models. Supplement of 2-AG further induced lipid accumulation and fibrogenesis through cannabinoid receptor type 2 (CB2)/β-catenin signaling. β-catenin knockout blocked 2-AG/CB2-induced fatty acid β-oxidation (FAO) deficiency and lipid accumulation. Remarkably, MAGL significantly decreased in CKD, aligning with lipid accumulation and fibrosis. Specific transgene of MAGL in tubular cells significantly preserved FAO, inhibited lipid-mediated toxicity in tubular cells, and finally retarded fibrogenesis. Additionally, supplementation of MAGL in UIRI mice also preserved FAO function, inhibited lipid accumulation, and protected against renal fibrosis. Conclusion: MAGL is a potential diagnostic marker for kidney function decline, and also serves as a new therapeutic target for renal fibrosis through ameliorating lipotoxicity.

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

Ren¹,

Cui²,

Wang³

et al. 2023

Biomedicine & Pharmacotherapy

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Kruppel‐like factor 4 improves obesity‐related nephropathy through increasing mitochondrial biogenesis and activities

Cited by 6 publications

References 33 publications

Palmitic acid up regulates Gal‑3 and induces insulin resistance in macrophages by mediating the balance between KLF4 and NF‑κB

Palmitic acid up regulates Gal‑3 and induces insulin resistance in macrophages by mediating the balance between KLF4 and NF‑κB

MAGL protects against renal fibrosis through inhibiting tubular cell lipotoxicity

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

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