Usefulness of Serum Leucine-Rich Alpha-2 Glycoprotein as a Disease Activity Biomarker in Patients with Rheumatoid Arthritis

Ha, You‐Jung; Kang, Eun Jin; Lee, Sang Won; Lee, Soo Kon; Park, Yong Bum; Song, Jung Soo; Choi, Sang Tae

doi:10.3346/jkms.2014.29.9.1199

Cited by 43 publications

(34 citation statements)

References 30 publications

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“…As secreted glycoprotein, LRG1 levels have been shown to increase in the plasma and urine of patients with a variety of cancer malignancies [26][27][28][29] and inflammatory diseases. [62][63][64][65] Our findings in the BioMe cohort, consisting of mixed races of Western patients with diabetes, indicate that plasma LRG1 is associated with renal outcome. Of note, during the preparation of this report, similar findings regarding plasma LRG1 were reported in a T2DM patient cohort in Singapore by Liu et al 66 Thus, the prognostic role of LRG1 in DKD progression has been confirmed in two separate patient cohorts, further strengthening our observations and confirming the human relevance of LRG1 in the pathogenesis of DKD.…”

Section: Discussionmentioning

confidence: 63%

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

Hong

Lü

et al. 2019

JASN

104

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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: 63%

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

Hong

Lü

et al. 2019

JASN

104

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“…In active LN, the inflammatory and autoimmune reactions were more serious. In previous study, serum LRG1 concentrations correlated with disease activity in SLE, rheumatoid arthritis, Crohn's disease, ulcerative colitis and adult-onset Still's disease [12,20,22,24,32].…”

Section: Discussionmentioning

confidence: 80%

“…The precise function of LRG1 remains unknown, but accumulating evidences showed that LRG1 is closely correlated with various types of cancers, such as lung, oral, ovarian, gastrict, pancreatic and biliary tract cancers [14][15][16][17][18]. Moreover, LRG1 is identified as an inflammatory protein in human serum and highly expressed in various kinds of benign inflammatory and autoimmune diseases, including suspected acute appendicitis of children [19], activated ulcerative colitis [12], rheumatoid arthritis [20,21], adultonset Still's disease [22] and asthma [23]. Especially, Ahn et al found serum LRG, namely LRG1, is elevated in patients with SLE and correlates with disease activity [24].…”

Section: Introductionmentioning

confidence: 99%

Leucine-rich α2-glycoprotein-1 upregulation in plasma and kidney of patients with lupus nephritis

et al. 2020

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Background: Increased leucine-rich α2-glycoprotein-1 (LRG1) has been observed in various inflammatory and autoimmune diseases. We aimed to explore the expression and role of LRG1 in lupus nephritis (LN). Methods: Plasma LRG1 (pLRG1) was measured by enzyme-linked immunosorbent assay in 101 patients with renal biopsy-proven LN and 21 healthy controls (HC). Relationships between pLRG1 and clinical and pathological characteristics were analyzed. The expression of LRG1 in peripheral blood leukocytes and kidney was detected by flow cytometry, immunohistochemistry and immunofluorescence, respectively. Further cell experiments were focused on the role of LRG1.Results: We found that LRG1 was expressed in plasma, some peripheral blood leukocytes, proximal tubule and several inflammatory cells. The levels of LRG1 in plasma, peripheral blood leukocytes and kidney were elevated in LN patients as compared to HC. Plasma expression levels of LRG1 correlated positively with renal function and renal disease activity, and reflect specific pathologic lesions in the kidneys of patients with LN. Interleukin-1β and interleukin-6, not tumor necrosis factor-α and interferon γ induced the LRG1 expression in human renal tubular epithelial cell line. Moreover, stimulation of recombinant human LRG1 could inhibit late apoptosis, promote proliferation and regulate expression of inflammatory factors and cytokines. Conclusions: Plasma expression levels of LRG1 were associated with renal function, disease activity, and pathology in LN. It might also be involved in renal inflammation, proliferation and apoptosis of endothelial cells. LRG1 might be a potential prognosis novel predictor in LN patients.

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“…It is induced in the liver by the pro-inflammatory cytokine IL-6. 17) Further, serum levels of LRG1 are elevated in patients with rheumatoid arthritis or ulcerative colitis. 18,19) As already mentioned, elevation of preoperative serum CRP and sIL-6R levels is related to poor PCRT response in patients with resectable esophageal cancer.…”

Section: Discussionmentioning

confidence: 99%

Leucine-Rich Alpha-2-Glycoprotein 1 in Serum Is a Possible Biomarker to Predict Response to Preoperative Chemoradiotherapy for Esophageal Cancer

Nambu

Masuda

Ito

et al. 2019

Biological & Pharmaceutical Bulletin

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The purpose of the present study was to identify a biomarker that can predict the response to preoperative chemoradiotherapy (PCRT) in esophageal cancer patients. Twenty-five serum samples collected from patents with esophageal cancer before PCRT (responder 13, non-responder 12) were analyzed by quantitative proteomics, and 248 proteins were identified. Among them, the serum levels of leucine-rich alpha-2-glycoprotein 1 (LRG1) were significantly different (p < 0.01) and well discriminated (area under the curve (AUC) of the receiver operating characteristic (ROC) curve >0.8) between responder and nonresponder groups. The combination of LRG1 with C-reactive protein (CRP) and soluble interleukin-6 receptor (sIL-6R), which were previously reported as biomarkers predicting PCRT response, further improved the predictive performance, providing an AUC of greater than 0.9. The present results suggest that LRG1 and its combination with CRP and sIL-6R are promising biomarker candidates to predict response to PCRT in esophageal cancer patients.

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Usefulness of Serum Leucine-Rich Alpha-2 Glycoprotein as a Disease Activity Biomarker in Patients with Rheumatoid Arthritis

Cited by 43 publications

References 30 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

Leucine-rich α2-glycoprotein-1 upregulation in plasma and kidney of patients with lupus nephritis

Leucine-Rich Alpha-2-Glycoprotein 1 in Serum Is a Possible Biomarker to Predict Response to Preoperative Chemoradiotherapy for Esophageal Cancer

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