TNF-α-induced LRG1 promotes angiogenesis and mesenchymal stem cell migration in the subchondral bone during osteoarthritis

Wang, Yiyun; Xu, Jiajia; Zhang, Xudong; Wang, Chuandong; Huang, Yan; Dai, Kerong; Xiao-ling, Zhang

doi:10.1038/cddis.2017.129

Cited by 132 publications

(119 citation statements)

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“…A recent study also showed that TNF-a induces LRG1 expression to promote angiogenesis and mesenchymal stem cell migration in the subchondral bone of osteoarthritis joints. 53 In silico analysis of LRG1 promoter indeed indicated multiple potential binding sites for p65 NF-kB and STAT3 transcription factors. Thus, it is plausible that the inflammatory cytokines known to be involved in the progression of DKD, such as TNF-a and IL-6, 54 may also participate in LRG1 upregulation in diabetic kidneys.…”

Section: Discussionmentioning

confidence: 98%

LRG1 Promotes Diabetic Kidney Disease Progression by Enhancing TGF-β–Induced Angiogenesis

Hong

Lü

et al. 2019

JASN

102

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Background Glomerular endothelial dysfunction and neoangiogenesis have long been implicated in the pathogenesis of diabetic kidney disease (DKD). However, the specific molecular pathways contributing to these processes in the early stages of DKD are not well understood. Our recent transcriptomic profiling of glomerular endothelial cells identified a number of proangiogenic genes that were upregulated in diabetic mice, including leucine-rich a-2-glycoprotein 1 (LRG1). LRG1 was previously shown to promote neovascularization in mouse models of ocular disease by potentiating endothelial TGF-b/activin receptorlike kinase 1 (ALK1) signaling. However, LRG1's role in the kidney, particularly in the setting of DKD, has been unclear.Methods We analyzed expression of LRG1 mRNA in glomeruli of diabetic kidneys and assessed its localization by RNA in situ hybridization. We examined the effects of genetic ablation of Lrg1 on DKD progression in unilaterally nephrectomized, streptozotocin-induced diabetic mice at 12 and 20 weeks after diabetes induction. We also assessed whether plasma LRG1 was associated with renal outcome in patients with type 2 diabetes.Results LRG1 localized predominantly to glomerular endothelial cells, and its expression was elevated in the diabetic kidneys. LRG1 ablation markedly attenuated diabetes-induced glomerular angiogenesis, podocyte loss, and the development of diabetic glomerulopathy. These improvements were associated with reduced ALK1-Smad1/5/8 activation in glomeruli of diabetic mice. Moreover, increased plasma LRG1 was associated with worse renal outcome in patients with type 2 diabetes.Conclusions These findings identify LRG1 as a potential novel pathogenic mediator of diabetic glomerular neoangiogenesis and a risk factor in DKD progression.Diabetic kidney disease (DKD) is a frequent complication of diabetes mellitus (DM) and the most common cause of ESRD in the United States. 1 Intensive glycemic control, BP control, and blockade of the renin-angiotensin-aldosterone system are the gold standard for current treatment of patients with DKD. 2-4 However, these established regimens provide only partial therapeutic effects, 5 indicating that pathogenic mechanisms driving DKD progression may not be targeted by current treatments. In addition, several recent clinical trials in DKD treatments were unsuccessful, 5-8 highlighting an unmet need for better understanding of mechanisms mediating the early stages of DKD for the design of novel preventive therapeutic strategies.Lrg1 expression that colocalize with CD31 outside the tubules. Scale bars, 20 mm. (D) Semiquantitative scoring of Lrg1 mRNA colocalized with Pecam mRNA (n=3 mice per group, 20 gloms scored per mouse). (E) In situ hybridization of LRG1 mRNA (red) combined with CD31 immunofluorescence (green) on human kidney sections with nuclear counterstain. Glomeruli are outlined with dotted lines on upper panels, and magnified view of the box is shown in lower panels. Scale bar, 50 mm. (F) Semiquantitative scoring of LRG1 mRNA colocalized with CD31...

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Section: Discussionmentioning

confidence: 98%

LRG1 Promotes Diabetic Kidney Disease Progression by Enhancing TGF-β–Induced Angiogenesis

Hong

Lü

et al. 2019

JASN

102

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“…Wang, Xu et al, 2017). It can significantly attenuate the severity of arthritis and joint damage by significantly reducing the production of serum anti-complement II (CII), tumor necrosis factor alpha (TNF-α), IL-1β, and IL-6 (Li, Tan, Wang, & Li, 2017;Y. Wang, Xu et al, 2017).…”

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confidence: 99%

“…In murine hippocampal HT22 cells, it was found that AP induced the expression and translocation of Nrf2 from the cytoplasm to the nucleus, thereby activating ARE gene transcription and heme oxygenase (HO-1) expression (Y. Wang, Xu et al, 2017). These findings led to an assertion that AP attenuates the progression of OA through its potential antioxidant effects by regulating the Keap1-Nrf2-ARE signaling pathway.…”

mentioning

confidence: 99%

Andrographolide protects chondrocytes from oxidative stress injury by activation of the Keap1–Nrf2–Are signaling pathway

Jiang

Liu

et al. 2018

Journal Cellular Physiology

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Recent studies have shown that andrographolide (AP) has the potential to be developed as a drug for therapy for osteoarthritis (OA). However, the role of AP in attenuating the progression of OA is still unknown. We hypothesized that its therapeutic effect may be associated with its antioxidant potential. In this study, we investigated the therapeutic effect of AP on chondrocytes injured by H O and the association with the oxidation-related signaling pathways through the detection of cell proliferation, cell viability, the expression of oxidative stress-specific genes (Sod1, Cat, and malonaldehyde [Mda]) and proteins (superoxide dismutase [SOD], catalase [CAT]) after a culture period of 3 and 5 days, respectively. Further exploration of the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) messenger RNA and protein was also performed. The results showed that 0.625 µg/ml and 2.5 µg/ml of AP decreased oxidative stress injury of chondrocytes by increasing cell proliferation reduced by H O and antioxidant enzyme activity, including SOD and CAT. Inflammation factors, such as matrix metallopeptidase 13 (Mmp13), tissue inhibitor of metalloproteinase 1 (Timp1), and interleukin-6 (Il6), were downregulated in the H O group with AP, demonstrating a decrease in the progression of OA. Pathway analyses identified that the kelch-like ECH-associated protein 1 (Keap1)-Nrf2-antioxidant response element (Are) pathway is an important mediator in AP therapy on H O -induced OA. This study indicates that AP exerts protection effects on oxidative stress via activation of the Keap1-Nrf2-Are pathway in chondrocytes injured by H O , which may be promising for the therapy of OA.

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“…In the present study, PRP increased plasma levels of TNFα, which might induce angiogenesis because of its mutual interaction with platelet‐activating factor present in PRP (Montrucchio et al, ), or due to the induction of mediators like LRG1 that promotes angiogenesis and mesenchymal stem cell migration (Wang et al, ). In addition, PRP also increased GRO‐α.…”

Section: Discussionmentioning

confidence: 72%

Effect of autologous transplant of peripheral blood mononuclear cells in combination with proangiogenic factors during experimental revascularization of lower limb ischemia

Padilla

Argüero‐Sánchez

Rodríguez-Trejo

et al. 2020

J Tissue Eng Regen Med

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Peripheral blood mononuclear cells (PBMCs) contain a cell fraction of mononuclear progenitor cells (MPCs), which own significant angiogenic potential. Autologous transplant of PBMC and/or platelet-rich plasma (PRP) promotes endothelial cells differentiation in experimental lower limb ischemia, which is considered a safe and effective strategy to support revascularization, either in animal models or clinical trials. In addition, thrombin has been proposed to enrich biological scaffolds, hence increasing MPC viability after intramuscular administration, whereas proangiogenic mediators such as vascular endothelial growth factor (VEGF), tumor necrosis factor alpha (TNF-α), inhibitor of the plasminogen activator-1 (PAI-1), and chemokine (CXCL1; GRO-α) participate in the endothelial response to ischemia, through their proangiogenic effects over endothelial cells proliferation, survival, migration, endothelial integrity maintenance, and physiologic vascular response to injury. In the present study, we describe the effect of autologous PBMCs transplant and PRP, either with or without thrombin, over proangiogenic mediators (measured by enzyme-linked immunosorbent assay) and revascularization response (angiographic vascular pattern at 30 days after vascular occlusion) in a rat model of lower limb ischemia. The group treated with PBMC + PRP significantly induced PAI-1, an effect that was prevented by the addition of thrombin. Furthermore, treatment with PBMC + PRP + thrombin resulted in the induction of VEGF. GRO-α showed a sensitive induction of all proangiogenic mediators. All treatments significantly stimulated revascularization, according to angiographic assessment, whereas higher effect was observed with PBMC + PRP treatment (p < .0001). In conclusion, autologous PBMC transplant stimulates revascularization during experimental ischemia of the lower limb, whereas

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TNF-α-induced LRG1 promotes angiogenesis and mesenchymal stem cell migration in the subchondral bone during osteoarthritis

Cited by 132 publications

References 44 publications

LRG1 Promotes Diabetic Kidney Disease Progression by Enhancing TGF-β–Induced Angiogenesis

LRG1 Promotes Diabetic Kidney Disease Progression by Enhancing TGF-β–Induced Angiogenesis

Andrographolide protects chondrocytes from oxidative stress injury by activation of the Keap1–Nrf2–Are signaling pathway

Effect of autologous transplant of peripheral blood mononuclear cells in combination with proangiogenic factors during experimental revascularization of lower limb ischemia

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