Oxidized low-density lipoprotein potentiates angiotensin II-induced Gq activation through the AT1-LOX1 receptor complex: Implications for renal dysfunction DOI Creative Commons

Jittoku Ihara,

Yibin Huang, Yoichi Takami

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: May 14, 2024

Abstract Chronic kidney disease (CKD) and atherosclerotic heart disease, frequently associated with dyslipidemia hypertension, represent significant health concerns. We investigated the interplay among these conditions, focusing on role of oxidized low-density lipoprotein (oxLDL) angiotensin II (Ang II) in renal injury via G protein αq subunit (Gq) signaling. hypothesized that oxLDL enhances Ang II-induced Gq signaling AT1 type 1 receptor)-LOX1 (lectin-like receptor) complex. Based CHO cell model experiments, alone did not activate However, when combined II, it significantly potentiated Gq-mediated inositol phosphate production calcium influx cells expressing both LOX-1 but AT1-expressing cells. This suggests a critical synergistic interaction between AT1-LOX1 Conformational studies using biosensors have indicated unique receptor conformational change due to oxLDL-Ang combination. In vivo, wild-type mice fed high-fat diet infusion presented exacerbated dysfunction, whereas knockout not, underscoring pathophysiological relevance damage. These findings highlight novel mechanism dysfunction CKD driven by hypertension suggest therapeutic potential complex patients comorbidities.

Language: Английский

Landscape analysis of m6A modification regulators reveals LRPPRC as a key modulator in tubule cells for DKD: a multi-omics study DOI Creative Commons
Li Jiang, Haijun Yu,

Jie Jian

et al.

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

Published: April 4, 2025

Background Diabetic Kidney Disease (DKD) is a serious complication of diabetes, imposing substantial medical burden. The significance N6-methyladenosine (m6A) modification in the pathogenesis DKD has become increasingly prominent. Aim This study aimed to investigate specific expression patterns m6A geneset DKD. Method Bulk RNA, single-cell and spatial transcriptome were utilized clarify hub gene. 3 types machine learning algorithms applied. possible compounds screened based on DSigDB database. Result GSEA revealed potential m6a-associated pathways such as cGMP-PKG pathway. GSVA showed that two m6a regulation, namely m6a-readers m6a-writers, generally suppressed patients. output algorithm differential analysis determined LRPPRC was downregulated LOH, PODO, CT, CD-ICB cell populations, most which tubular cells. It exhibited decreasing trend over time, particularly pronounced LOH low activity mainly detected injured renal tubules. In clinical patients, levels mRNA tendency be correlations with Glomerular Filtration Rate (GFR) proteinuria according Nephroseq lobeline might an important compound involved regulation other genes. Its actual efficacy needs verified vivo or vitro .

Language: Английский

Citations

0
Transcriptional Intermediary Factor 1γ–Induced Irisin in Skeletal Muscle Attenuates Renal Fibrosis in Diabetic Nephropathy DOI Creative Commons
Jin Hyun Kim, Seunghye Lee, Ha Nee Jang

et al.

Journal of Cachexia Sarcopenia and Muscle, Journal Year: 2025, Volume and Issue: 16(2)

Published: April 1, 2025

Language: Английский

Citations

0
Single-cell analysis of proximal tubular cells with different DNA content reveals functional heterogeneity in the acute kidney injury to chronic kidney disease transition DOI
Fugang Li, Qigang Lan, Yaqin Wang

et al.

Kidney International, Journal Year: 2025, Volume and Issue: unknown

Published: April 1, 2025

Language: Английский

Citations

0
F-box only protein 10 protects against kidney tubulointerstitial fibrosis by inhibiting ACSL4-mediated lipid peroxidation and ferroptosis DOI
Jinping Hu,

Feng Ma,

Xinping Chen

et al.

Cellular Signalling, Journal Year: 2025, Volume and Issue: unknown, P. 111841 - 111841

Published: April 1, 2025

Language: Английский

Citations

0
Continuous genetic monitoring of transient mesenchymal gene activities in distal tubule and collecting duct epithelial cells during renal fibrosis DOI

Zihang Xu,

Shaotong Zhang, Tingting Han

et al.

Journal of Cellular Biochemistry, Journal Year: 2024, Volume and Issue: 125(4)

Published: Feb. 19, 2024

Abstract Epithelial cells (ECs) have been proposed to contribute myofibroblasts or fibroblasts through epithelial‐mesenchymal transition (EMT) during renal fibrosis. However, since EMT may occur dynamically, transiently, and reversibly kidney fibrosis, conventional lineage tracing based on Cre‐loxP recombination in ECs could hardly capture the transient activity, yielding inconsistent results. Moreover, previous research has primarily focused proximal tubule ECs, with few reports of distal tubules collecting ducts. Here, we generated dual recombinases‐mediated genetic systems for continuous monitoring mesenchymal gene expression E‐cadherin + EpCAM ducts Activation key EMT‐inducing transcription factor (EMT‐TF) Zeb1 markers αSMA, vimentin, N‐cadherin, were investigated following unilateral ureteral obstruction (UUO). Our data revealed that did not transdifferentiate into myofibroblasts, nor transiently expressed these genes In contrast, vitro a large amount cultured upregulated response TGF‐β, major inducer EMT.

Language: Английский

Citations

3
Anti-Inflammatory Role of the Klotho Protein and Relevance to Aging DOI Open Access
Gérald J. Prud’homme, Qinghua Wang

Published: Aug. 5, 2024

The α-Klotho protein (hereafter Klotho) is an obligate coreceptor for fibroblast growth factor 23 (FGF23). It produced in the kidneys, brain and other sites. Klotho insufficiency causes hyperphosphatemia anomalies. Importantly, it associated with chronic pathologies (often age-related) that have inflammatory component. This includes atherosclerosis, diabetes Alzheimer’s disease. Its mode of action these diseases not well understood, but inhibits or regulates multiple major pathways. has a membrane form, soluble form (s-Klotho). Cytosolic postulated characterized. s-Klotho endocrine properties are incompletely elucidated. binds to FGF receptor 1c (FGFR1c) widely expressed (including endothelial cells). also attaches FGF23, FGF23/Klotho FGFRs. Thus, might be roaming FGF23 coreceptor, functions. Notably, (cell-bound soluble) counteracts inflammation, appears mitigate related aging (inflammaging). NF-κB NLRP3 inflammasome. inflammasome requires priming by NF-κB, produces active IL-1β, pores cell death (pyroptosis). In accord, countered inflammation injury induced toxins, damage-associated molecular patterns (DAMPs), cytokines, reactive oxygen species (ROS). blocks TGF-β Wnt ligands, which lessens fibrotic Low loss muscle mass (sarcopenia), as occurs diseases. counters inhibitory effects myostatin on muscle, reduces improves repair following injury. Inhibition factors may protective diabetic retinopathy age-related macular degeneration (AMD). review examines functions especially potential applications.

Language: Английский

Citations

3
Intestinal Fibrogenesis in Inflammatory Bowel Diseases: Exploring the Potential Role of Gut Microbiota Metabolites as Modulators DOI Creative Commons
Sara Cicchinelli, Stefania Gemma, Giulia Pignataro

et al.

Pharmaceuticals, Journal Year: 2024, Volume and Issue: 17(4), P. 490 - 490

Published: April 11, 2024

Fibrosis, sustained by the transformation of intestinal epithelial cells into fibroblasts (epithelial-to-mesenchymal transition, EMT), has been extensively studied in recent decades, with molecular basis well-documented various diseases, including inflammatory bowel diseases (IBDs). However, factors influencing these pathways remain unclear. In years, role gut microbiota health and disease garnered significant attention. Evidence suggests that an imbalanced or dysregulated microbiota, along environmental genetic factors, may contribute to development IBDs. Notably, microbes produce metabolites interact host receptors associated signaling pathways, physiological pathological changes. This review aims present evidence highlighting emerging most as potential modulators implicated fibrosis EMT These studies provide a deeper understanding inflammation fibrosis, elucidating IBDs, paving way for future treatments.

Language: Английский

Citations

2
Up-regulation of long non-coding RNA H19 ameliorates renal tubulointerstitial fibrosis by reducing lipid deposition and inflammatory response through regulation of the microRNA-130a-3p/long-chain acyl-CoA synthetase 1 axis DOI Creative Commons
Yali Jiang,

Feng Ma,

Jing Wang

et al.

Non-coding RNA Research, Journal Year: 2024, Volume and Issue: 9(4), P. 1120 - 1132

Published: May 9, 2024

Long non-coding RNA (lncRNA) H19 is an extensively studied lncRNA that related to numerous pathological changes. Our previous findings have documented serum levels are decreased in patients with chronic kidney disorder and reduction closely correlated renal tubulointerstitial fibrosis, essential step developing end-stage disease. Nonetheless, the precise function mechanism of fibrosis not fully comprehended. The present work utilized a mouse model unilateral ureteral obstruction (UUO) transforming growth factor-β1 (TGF-β1)-stimulated HK-2 cells investigate possible role were investigated. Levels kidneys mice UUO stimulated TGF-β1. Up-regulation remarkably relieved injury, inflammation triggered by UUO. Moreover, increase reduced epithelial-to-mesenchymal transition (EMT) induced Notably, up-regulation lipid accumulation triacylglycerol content TGF-β1-stimulated cells, accompanied long-chain acyl-CoA synthetase 1 (ACSL1). was identified as sponge microRNA-130a-3p, through which modulates expression ACSL1. overexpression microRNA-130a-3p reversed H19-induced increases suppressive effects on EMT, diminished ACSL1 silencing or overexpression. Overall, showed ameliorated reducing deposition via modulation microRNA-130a-3p/ACSL1 axis.

Language: Английский

Citations

2
Deciphering the molecular nexus of BTG2 in periodontitis and diabetic kidney disease DOI Creative Commons
Binhui Pan, Yangyang Teng,

Renban Wang

et al.

BMC Medical Genomics, Journal Year: 2024, Volume and Issue: 17(1)

Published: June 3, 2024

Abstract Objective To investigate the role of BTG2 in periodontitis and diabetic kidney disease (DKD) its potential underlying mechanism. Methods Gene expression data for DKD were acquired from Expression Omnibus (GEO) database. Differential analysis identified co-expressed genes between these conditions. The Nephroseq V5 online nephropathy database validated DKD. Pearson correlation associated with our target gene. We employed Set Enrichment Analysis (GSEA) Protein-Protein Interaction (PPI) networks to elucidate mechanisms. levels mRNA examined using quantitative polymerase Chain Reaction (qPCR) immunofluorescence assays. Western blotting quantified proteins involved epithelial-to-mesenchymal transition (EMT), apoptosis, mTORC1 signaling, autophagy. Additionally, wound healing flow cytometric apoptosis assays evaluated podocyte migration respectively. Results GEO revealed as a commonly differentially expressed gene both periodontitis. was reduced compared normal conditions correlated proteinuria. GSEA indicated enrichment EMT signaling pathways. PPI network highlighted BTG2’s relevance S100A9, S100A12, FPR1. Immunofluorescence demonstrated significantly lower podocytes under high glucose (HG) Reduced HG-treated led increased markers (α-SMA, vimentin) apoptotic protein Bim, alongside decrease nephrin. Lower mobility well elevated RPS6KB1 mTOR levels, but autophagy marker LC3. Conclusion Our findings suggest that is crucial intermediary linking Modulating via inhibition pathway, consequently suppressing EMT, may be pivotal interplay

Language: Английский

Citations

1
α-Mangostin reduces hypertension in spontaneously hypertensive rats and inhibits EMT and fibrosis in Ang II-induced HK-2 cells DOI Creative Commons

Yuhui Xu,

Jianhua Wu, Lihui Gao

et al.

International Journal of Medical Sciences, Journal Year: 2024, Volume and Issue: 21(9), P. 1681 - 1688

Published: Jan. 1, 2024

Hypertension affects a large number of individuals globally and is common cause nephropathy, stroke, ischaemic heart disease other vascular diseases. While many anti-hypertensive medications are used safely effectively in clinic practice, controlling hypertensive complications solely by reducing blood pressure (BP) can be challenging. α-Mangostin, xanthone molecule extracted from the pericarp

Language: Английский

Citations

1