Identification of AnnexinA1 as an Endogenous Regulator of RhoA, and Its Role in the Pathophysiology and Experimental Therapy of Type-2 Diabetes

Purvis, Gareth S. D.; Collino, Massimo; Loiola, Rodrigo Azevedo; Baragetti, Andrea; Chiazza, Fausto; Brovelli, Martina; Sheikh, Madeeha H; Collotta, Debora; Cento, Alessia Sofia; Mastrocola, Raffaella; Aragno, Manuela; Cutrìn, Juan Carlos; Reutelingsperger, Chris; Grigore, Liliana; Catapano, Alberico L.; Yaqoob, Magdi; Norata, Giuseppe Danilo; Solito, Egle; Thiemermann, Christoph

doi:10.3389/fimmu.2019.00571

Cited by 46 publications

(54 citation statements)

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“…In addition, VWF was reported to be involved in intrarenal thrombosis leading to the deterioration of renal function 22 . Purvis et al observed higher circulating plasma levels of ANXA1 in T1D and T2D patients, whereas the exogenous supplementation of ANXA1 improves insulin resistance and prevents the progression of subsequent microvascular complications in mice 23 , 24 . Previous studies have demonstrated that statins prevent DN by reducing the activity of Ras homolog family member A (RhoA) protein activation 25 – 28 .…”

Section: Discussionmentioning

confidence: 99%

Identification of C3 as a therapeutic target for diabetic nephropathy by bioinformatics analysis

Tang

Wang

Deng

et al. 2020

Sci Rep

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The pathogenesis of diabetic nephropathy is not completely understood, and the effects of existing treatments are not satisfactory. Various public platforms already contain extensive data for deeper bioinformatics analysis. From the GSE30529 dataset based on diabetic nephropathy tubular samples, we identified 345 genes through differential expression analysis and weighted gene coexpression correlation network analysis. GO annotations mainly included neutrophil activation, regulation of immune effector process, positive regulation of cytokine production and neutrophil-mediated immunity. KEGG pathways mostly included phagosome, complement and coagulation cascades, cell adhesion molecules and the AGE-RAGE signalling pathway in diabetic complications. Additional datasets were analysed to understand the mechanisms of differential gene expression from an epigenetic perspective. Differentially expressed miRNAs were obtained to construct a miRNA-mRNA network from the miRNA profiles in the GSE57674 dataset. The miR-1237-3p/SH2B3, miR-1238-5p/ ZNF652 and miR-766-3p/TGFBI axes may be involved in diabetic nephropathy. The methylation levels of the 345 genes were also tested based on the gene methylation profiles of the GSE121820 dataset. The top 20 hub genes in the PPI network were discerned using the CytoHubba tool. Correlation analysis with GFR showed that SYK, CXCL1, LYN, VWF, ANXA1, C3, HLA-E, RHOA, SERPING1, EGF and KNG1 may be involved in diabetic nephropathy. Eight small molecule compounds were identified as potential therapeutic drugs using Connectivity Map. It is estimated that a total of 451 million people suffered from diabetes by 2017, and the number is speculated to be 693 million by 2045 1. As one of the most serious microvascular complications, diabetic nephropathy (DN) has been a major cause of end-stage renal disease (ESRD) in many countries. The congregation of advanced glycation end-products, oxidative stress and activation of protein kinase C are the major pathogeneses of DN. A new viewpoint holds that tubular injury plays an important and even initial role 2. Current treatment strategies for DN aim at controlling blood glucose and blood pressure levels and inhibiting the RAS system to reduce albuminuria and delay the progression of DN 3. However, considering the high incidence of DN-related ESRD, the effect is not entirely satisfactory. Therefore, there is a critical need to identify new therapeutic targets and improve clinical management. High-throughput sequencing technology offers an effective method to study disease-related genes and provides promising medication goals in many fields 4. To date, several studies have screened genes or miRNAs involved in DN 5-9. Integrating these data could overcome the heterogeneity of studies and provide more accurate information. This study identified target genes that may improve the understanding of the molecular mechanisms of DN and provide a resource to build new hypotheses for further follow-up studies. We suggest that the complement system may serve as a thera...

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Section: Discussionmentioning

confidence: 99%

Identification of C3 as a therapeutic target for diabetic nephropathy by bioinformatics analysis

Tang

Wang

Deng

et al. 2020

Sci Rep

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“…Then sections were then dehydrated through graded alcohols and cleared before mounting with coverslips. Images were acquired using a NanoZoomer Digital Pathology Scanner and analysed using the NDP Viewer software (Purvis et al, 2019).…”

Section: Periodic Acid Schiff's Stainingmentioning

confidence: 99%

Inhibition of Bruton's TK regulates macrophage NF‐κB and NLRP3 inflammasome activation in metabolic inflammation

Purvis

Collino

Aranda-Tavío

et al. 2020

British J Pharmacology

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Background and Purpose There are no medications currently available to treat metabolic inflammation. Bruton's tyrosine kinase (BTK) is highly expressed in monocytes and macrophages and regulates NF‐κB and NLRP3 inflammasome activity; both propagate metabolic inflammation in diet‐induced obesity. Experimental Approach Using an in vivo model of chronic inflammation, high‐fat diet (HFD) feeding, in male C57BL/6J mice and in vitro assays in primary murine and human macrophages, we investigated if ibrutinib, an FDA approved BTK inhibitor, may represent a novel anti‐inflammatory medication to treat metabolic inflammation. Key Results HFD‐feeding was associated with increased BTK expression and activation, which was significantly correlated with monocyte/macrophage accumulation in the liver, adipose tissue, and kidney. Ibrutinib treatment to HFD‐fed mice inhibited the activation of BTK and reduced monocyte/macrophage recruitment to the liver, adipose tissue, and kidney. Ibrutinib treatment to HFD‐fed mice decreased the activation of NF‐κB and the NLRP3 inflammasome. As a result, ibrutinib treated mice fed HFD had improved glycaemic control through restored signalling by the IRS‐1/Akt/GSK‐3β pathway, protecting mice against the development of hepatosteatosis and proteinuria. We show that BTK regulates NF‐κB and the NLRP3 inflammasome specifically in primary murine and human macrophages, the in vivo cellular target of ibrutinib. Conclusion and Implications We provide “proof of concept” evidence that BTK is a novel therapeutic target for the treatment of diet‐induced metabolic inflammation and ibrutinib may be a candidate for drug repurposing as an anti‐inflammatory agent for the treatment of metabolic inflammation in T2D and microvascular disease.

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“…In addition, the levels of ANXA1 in T2D patients are positively correlated with serum low-density lipoprotein cholesterol (LDL-C) levels, total cholesterol levels, and the fatty liver index (FLI). ANXA1−/− mice have significantly higher serum triglyceride levels, more extensive Oil Red-O staining in the liver, and are more obese than wild-type mice, and administration of hrANXA1 to these mice reduces serum cholesterol and liver triglyceride levels, the extent of Oil Red-O staining in liver, and weight gain (Purvis et al 2019a ). These findings may suggest that ANXA1 is associated with lipid and glucose metabolism.…”

Section: Anxa1 Mediates Anti-inflammatory Effects Cholesterol Transpmentioning

confidence: 99%

The crosstalk of ABCA1 and ANXA1: a potential mechanism for protection against atherosclerosis

Shen

Zhang

Zhu

et al. 2020

Mol Med

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Atherosclerosis, characterized by the formation of fat-laden plaques, is a chronic inflammatory disease. ABCA1 promotes cholesterol efflux, reduces cellular cholesterol accumulation, and regulates anti-inflammatory activities in an apoA-I- or ANXA1-dependent manner. The latter activity occurs by mediating the efflux of ANXA1, which plays a critical role in anti-inflammatory effects, cholesterol transport, exosome and microparticle secretion, and apoptotic cell clearance. ApoA-I increases ANXA1 expression via the ERK, p38MAPK, AKT, and PKC pathways. ApoA-I regulates the signaling pathways by binding to ABCA1, suggesting that apoA-I increases ANXA1 expression by binding to ABCA1. Furthermore, ANXA1 may increase ABCA1 expression. ANXA1 increases PPARγ expression by modulating STAT6 phosphorylation. PPARγ also increases ANXA1 expression by binding to the promoter of ANXA1. Therefore, ABCA1, PPARγ, and ANXA1 may form a feedback loop and regulate each other. Interestingly, the ANXA1 needs to be externalized to the cell membrane or secreted into the extracellular fluids to exert its anti-inflammatory properties. ABCA1 transports ANXA1 from the cytoplasm to the cell membrane by regulating lipidization and serine phosphorylation, thereby mediating ANXA1 efflux, likely by promoting microparticle and exosome release. The direct role of ABCA1 expression and ANXA1 release in atherosclerosis has been unclear. In this review, we focus on the role of ANXA1 in atheroprogression and its novel interaction with ABCA1, which may be useful for providing basic knowledge for the development of novel therapeutic targets for atherosclerosis and cardiovascular disease.

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Identification of AnnexinA1 as an Endogenous Regulator of RhoA, and Its Role in the Pathophysiology and Experimental Therapy of Type-2 Diabetes

Cited by 46 publications

References 46 publications

Identification of C3 as a therapeutic target for diabetic nephropathy by bioinformatics analysis

Identification of C3 as a therapeutic target for diabetic nephropathy by bioinformatics analysis

Inhibition of Bruton's TK regulates macrophage NF‐κB and NLRP3 inflammasome activation in metabolic inflammation

The crosstalk of ABCA1 and ANXA1: a potential mechanism for protection against atherosclerosis

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