Hydroxychloroquine alleviates renal interstitial fibrosis by inhibiting the PI3K/Akt signaling pathway

Li, Dengren; Yu, Kuipeng; Feng, Feng; Zhang, Yang; Bai, Fang; Zhang, Yimeng; Sun, Nan; Fan, Jiahui; Liu, Lei; Yang, Huimin; Yang, Xiaoling

doi:10.1016/j.bbrc.2022.04.058

Cited by 14 publications

(8 citation statements)

References 32 publications

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“…The PI3K-AKT pathway contributes to the regulation of immune cell metabolism ( Yang et al, 2020 ), and JAK2-STAT3 pathway is widely considered to be involved in inflammation related diseases. In addition, it has been reported that HCQ may be involved in the regulation of these two pathways ( Lyu et al, 2020 ; Li et al, 2022 ). Our results showed that HCQ treatment inhibited the protein and mRNA expression of GRK2 ( Figures 7A,B ) and reversed the activated PI3K-AKT-mTOR pathway induced by S-100 in the liver ( Figure 7C ).…”

Section: Resultsmentioning

confidence: 99%

“…In addition, increasing PI3K produced polyphosphoinositides that interacted with protein kinases, leading to activation of the kinase AKT ( Saltiel, 2021 ). HCQ has been reported to inhibit PI3K-AKT pathway in renal interstitial fibrosis ( Li et al, 2022 ). Therefore, we tested whether HCQ inhibited the PI3K-AKT pathway by regulating the interaction between GRK2 and PI3K or AKT in T cells of AIH.…”

Section: Discussionmentioning

confidence: 99%

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Hydroxychloroquine attenuates autoimmune hepatitis by suppressing the interaction of GRK2 with PI3K in T lymphocytes

et al. 2022

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Hydroxychloroquine (HCQ) is derivative of the heterocyclic aromatic compound quinoline, which has been used for the treatment of autoimmune diseases. The central purpose of this study was to investigate therapeutic effects and inflammatory immunological molecular mechanism of HCQ in experimental autoimmune hepatitis (AIH). Treatment with HCQ ameliorated hepatic pathologic damage, inflammatory infiltration, while promoted regulatory T cell (Treg) and down-regulated CD8+T cell differentiation in AIH mice induced by S-100 antigen. In vitro, HCQ also suppressed pro-inflammatory cytokine (IFN-γ, TNF-α, and IL-12) secretion, promoted anti-inflammatory cytokine (TGF-β1) secretion. HCQ mainly impaired T cell lipid metabolism but not glycolysis to promote Treg differentiation and function. Mechanistically, HCQ down-regulated GRK2 membrane translocation in T cells, inhibited GRK2-PI3K interaction to reduce the PI3K recruiting to the membrane, followed by suppressing the phosphorylation of PI3K-AKT-mTOR signal. Pretreating T cells with paroxetine, a GRK2 inhibitor, disturbed HCQ effect to T cells. HCQ also reversed the activation of the PI3K-AKT axis by 740 Y-P (PI3K agonist). Meanwhile, HCQ inhibited the PI3K-AKT-mTOR, JAK2-STAT3-SOCS3 and increased the AMPK signals in the liver and T cells of AIH mice. In conclusion, HCQ exhibited specific and potent therapeutic effects on AIH and attendant liver injury, which was attributed to HCQ acted on GRK2 translocation, inhibited metabolism-related PI3K-AKT and inflammation-related JAK2-STAT3 signal in T lymphocytes, thereby modulating lipid metabolism of T cell function to regulate Treg differentiation and function.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Hydroxychloroquine attenuates autoimmune hepatitis by suppressing the interaction of GRK2 with PI3K in T lymphocytes

et al. 2022

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“…This may be a common mechanism of HCQ treatment for LN and IgAN. 31 Besides, in patients with IgAN, Th cell differentiation is a characteristic of the continuous immunological response. The more T cells were activated in peripheral blood and immune organs, the more IgA was produced by B lymphocytes.…”

Section: Discussionmentioning

confidence: 99%

“…We speculate that this could be a potential target for HCQ to play a protective role in LN and IgAN. 31 As a stress route of cellular functional activities, the MAPK signaling pathway plays an essential role in acute and chronic inflammation, as well as physiological processes such as cell growth, development, differentiation, and apoptosis. 32 Stimulation of the MAPK signaling pathway might cause both renal inflammation and podocyte damage.…”

Section: Discussionmentioning

confidence: 99%

Network pharmacology and molecular docking to elucidate the common mechanism of hydroxychloroquine treatment in lupus nephritis and IgA nephropathy

Chen,

Lu,

Lin

et al. 2024

Lupus

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Objective Hydroxychloroquine (HCQ), characterized by a broad effect on immune regulation, has been widely used in the treatment of autoimmune glomerulonephritis such as lupus nephritis (LN) and immunoglobulin A nephropathy (IgAN). The current research investigates whether HCQ plays a role in the treatment of LN and IgAN through common mechanisms since the pathogenesis of both LN and IgAN is closely related to immune complex deposition, complement activation, and ultimately inflammation. Methods Seventy-two common targets were obtained related to the common mechanism of HCQ treatment of LN and IgAN. Targets associated with LN and IgAN were collected based on DisGeNET, GeneCards, and OMIM databases. Possible HCQ targets were obtained from the PubChem database and PharmMapper databases. The overlapping targets of HCQ ingredients, IgAN, and LN were discovered via the Venn 2.1.0 online platform. Through the DAVID database, the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were conducted. Cytoscape (v3.9.1) was used to build a protein–protein interaction (PPI) network. Molecular docking was performed by using AutoDockTools 1.5.6 software and PyMol software to match the binding activity between HCQ and the 10 core targets. Results The results showed that core targets (including MMP 2, PPARG, IL-2, MAPK14, MMP 9, and SRC), three signaling pathways (including the PI3K-Akt, AGE-RAGE, and MAPK), and cell differentiation (including Th1, Th2, and Th17) might be related to the body’s immunity and inflammation. These results suggested that HCQ might act on targets and pathways involved in inflammation and immune regulation to exert a common effect on the treatment of LN and IgAN. Conclusions The current study provided new evidence for the protective mechanism and clinical utility of HCQ against LN and IgAN.

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“…GEO Database is a database established by the National Centre or Biotechnology Information (NCBI) to determine the critical genes and underlying molecular mechanisms for disease pathogenesis and progression (6). Recently, bioinformatics and machine learning methods extensively employed in biomarker screening by using the GEO database (7)(8)(9). What's more, secreted proteins have significance in course of biological activity, specifically in the diagnosis of diseases and future target therapies (10,11).…”

Section: Introductionmentioning

confidence: 99%

APOC1 as a novel diagnostic biomarker for DN based on machine learning algorithms and experiment

Wang

et al. 2023

Front. Endocrinol.

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IntroductionDiabetic nephropathy is the leading cause of end-stage renal disease, which imposes a huge economic burden on individuals and society, but effective and reliable diagnostic markers are still not available.MethodsDifferentially expressed genes (DEGs) were characterized and functional enrichment analysis was performed in DN patients. Meanwhile, a weighted gene co-expression network (WGCNA) was also constructed. For further, algorithms Lasso and SVM-RFE were applied to screening the DN core secreted genes. Lastly, WB, IHC, IF, and Elias experiments were applied to demonstrate the hub gene expression in DN, and the research results were confirmed in mouse models and clinical specimens.Results17 hub secretion genes were identified in this research by analyzing the DEGs, the important module genes in WGCNA, and the secretion genes. 6 hub secretory genes (APOC1, CCL21, INHBA, RNASE6, TGFBI, VEGFC) were obtained by Lasso and SVM-RFE algorithms. APOC1 was discovered to exhibit elevated expression in renal tissue of a DN mouse model, and APOC1 is probably a core secretory gene in DN. Clinical data demonstrate that APOC1 expression is associated significantly with proteinuria and GFR in DN patients. APOC1 expression in the serum of DN patients was 1.358±0.1292μg/ml, compared to 0.3683±0.08119μg/ml in the healthy population. APOC1 was significantly elevated in the sera of DN patients and the difference was statistical significant (P > 0.001). The ROC curve of APOC1 in DN gave an AUC = 92.5%, sensitivity = 95%, and specificity = 97% (P < 0.001).ConclusionsOur research indicates that APOC1 might be a novel diagnostic biomarker for diabetic nephropathy for the first time and suggest that APOC1 may be available as a candidate intervention target for DN.

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Hydroxychloroquine alleviates renal interstitial fibrosis by inhibiting the PI3K/Akt signaling pathway

Cited by 14 publications

References 32 publications

Hydroxychloroquine attenuates autoimmune hepatitis by suppressing the interaction of GRK2 with PI3K in T lymphocytes

Hydroxychloroquine attenuates autoimmune hepatitis by suppressing the interaction of GRK2 with PI3K in T lymphocytes

Network pharmacology and molecular docking to elucidate the common mechanism of hydroxychloroquine treatment in lupus nephritis and IgA nephropathy

APOC1 as a novel diagnostic biomarker for DN based on machine learning algorithms and experiment

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