Plasma Leucine-Rich α-2-Glycoprotein 1 Predicts Rapid eGFR Decline and Albuminuria Progression in Type 2 Diabetes Mellitus

Liu, Jing; Pek, Sharon Li Ting; Ang, Keven; Tavintharan, Subramaniam; Lim, Su Chi; study, Smart D

doi:10.1210/jc.2017-00930

Cited by 51 publications

(44 citation statements)

References 36 publications

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“…[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. Future studies are required to confirm the clinical implications of LRG1 and other angiogenesis factors in DKD, and to assess the efficacy of urinary LRG1 detection as a prognostic marker of DKD progression.…”

Section: Discussionsupporting

confidence: 90%

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: Discussionsupporting

confidence: 90%

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

Hong

Lü

et al. 2019

JASN

104

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“…LRG1 is upregulated in the glomerular endothelial cells isolated from streptozotocin-induced diabetic eNOS null mice as the model of diabetic nephropathy 32 . Moreover, LRG1 independently predicts the progression of albuminuria more strongly than traditional risk factors, including baseline eGFR and urine albumin to creatinine ratio 31 . In previous work, the level of plasma LRG1 was found to neither be affected by age nor by dialysis vintage on ESRD patients.…”

Section: Discussionmentioning

confidence: 93%

“…Recent studies showed that LRG1 promotes pathogenic neovascularization by binding to endoglin and subsequent activation of the TGF-β signaling pathway in endothelial cells 29,30 . In a 3-year prospective study of type 2 diabetes patients, a higher LRG1 level at baseline predicts higher risk for progression of albuminuria as well as eGFR decline independently 31 . LRG1 is upregulated in the glomerular endothelial cells isolated from streptozotocin-induced diabetic eNOS null mice as the model of diabetic nephropathy 32 .…”

Section: Discussionmentioning

confidence: 99%

Plasma Leucine-Rich α-2-Glycoprotein 1 Predicts Cardiovascular Disease Risk in End-Stage Renal Disease

Yang

Hsieh

Shu

et al. 2020

Sci Rep

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plasma leucine-Rich α-2-glycoprotein 1 (LRG1) is an innovative biomarker for inflammation and angiogenesis. Many adverse pathophysiological changes including inflammation, atherosclerosis, and premature mortality is associated with End-stage renal disease (ESRD). However, whether levels of plasma LRG1 correlate with the co-morbidities of ESRD patients is unknown. Plasma LRG1 and high-sensitivity C-reactive protein (hsCRP) were analyzed by ELISA in 169 hemodialysis patients from the Immunity in ESRD (iESRD) study. Patient demographics and comorbidities at the time of enrollment were recorded. Peripheral blood monocyte and T cell subsets were assessed by multicolor flow cytometry. In the univariate analysis, a higher level of LRG1 was associated with the presence of cardiovascular disease (CVD) and peripheral arterial occlusive disease (PAOD). In multivariate logistic regression models, higher LRG1 tertile was significantly associated with PAOD (odds ratio = 3.49) and CVD (odds ratio = 1.65), but not with coronary artery disease, history of myocardial infarction, or stroke after adjusting for gender, diabetes, hemoglobin, albumin, calcium-phosphate product, and level of hsCRP. In addition, the level of LRG1 had a positive correlation with IL-6, hsCRP, and also more advanced T cell differentiation. The association suggests that LRG1 participates in the progression of atherosclerosis by inducing inflammation. Therefore, the role of LRG1 in coexisting inflammatory response should be further investigated in the pathogenesis of cardiovascular morbidity and mortality in patients with ESRD. Cardiovascular mortality in patients with end-stage renal disease (ESRD) remains the leading cause of death 1,2. These patients exhibit a strikingly higher risk (20-400 folds) of cardiovascular mortality compared to age-matched health subjects without any kidney disease 3. Traditional risk factors as well as non-traditional risk factors, such as inflammation, are believed to contribute to the excessively heavy burden of cardiovascular disease in chronic kidney disease (CKD) and ESRD patients 3. The pro-inflammatory microenvironment is collectively caused by uremic milieu, infection, and tissue ischemia even before the initiation of dialysis 4. Innate immunity is the evolutionarily conserved host response mediated by pattern recognition receptors (PRRs), which bind endogenous or exogenous ligands and initiate downstream signaling pathways to establish an immediate responses as the first line of defense. Two types of PRRs, Toll-like receptors (TLRs) over the cell surface and inflammasomes in the cytoplasm can interact with endogenous ligands. They are involved in the development of pro-inflammatory microenvironment in renal failure. Activation of these innate immune pathways is

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“…Subsequent studies from our group and others have shown that LRG is increased in various immune-related diseases such as adult-onset Still's disease 19 , psoriasis 20 , juvenile idiopathic arthritis 21 , Kawasaki disease 22 , appendicitis 23 and cancers 24,25 , indicating that LRG elevation is not limited to autoimmune diseases. In addition, LRG may serve as a biomarker for several other disease conditions such as heart failure 26 , diabetes-related complications [27][28][29] and obesity 30 , which are not typical inflammatory www.nature.com/scientificreports www.nature.com/scientificreports/ diseases but may involve immunopathogenic mechanisms. Thus, for diagnosis of active TB, LRG should be used in conjunction with other laboratory tests such as IGRA.…”

Section: Discussionmentioning

confidence: 99%

Leucine-rich alpha 2 glycoprotein is a new marker for active disease of tuberculosis

Fujimoto

Matsumoto

Serada

et al. 2020

Sci Rep

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Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) is a global health problem. At present, prior exposure to Mtb can be determined by blood-based interferon-gamma release assay (IGRA), but active TB is not always detectable by blood tests such as CRP and ESR. This study was undertaken to investigate whether leucine-rich alpha-2 glycoprotein (LRG), a new inflammatory biomarker, could be used to assess active disease of TB. Cynomolgus macaques pretreated with or without Bacille Calmette-Guerin (BCG) vaccination were inoculated with Mtb to induce active TB. Blood was collected over time from these animals and levels of LRG as well as CRP and ESR were quantified. In the macaques without BCG vaccination, Mtb inoculation caused extensive TB and significantly increased plasma CRP and LRG levels, but not ESR. In the macaques with BCG vaccination, whereas Mtb challenge caused pulmonary TB, only LRG levels were significantly elevated. By immunohistochemical analysis of the lung, LRG was visualized in epithelioid cells and giant cells of the granulation tissue. In humans, serum LRG levels in TB patients were significantly higher than those in healthy controls and declined one month after anti-tubercular therapy. These findings suggest that LRG is a promising biomarker when performed following IGRA for the detection of active TB. Tuberculosis (TB) is a symptomatic disease caused by replicating Mycobacterium tuberculosis (Mtb). According to the WHO global tuberculosis report 2018 (https://www.who.int/tb/publications/global_report/en/), about 23% of the world's population is estimated to be latently infected with Mtb, Of these, up to 10% of humans develop active disease after Mtb infection 1 , which makes TB a major global health problem with the estimation of 10.4 million new cases and 1.7 million deaths in 2016 2. Importantly, 40% of estimated TB cases remain to be undiagnosed 2. Rapid detection of active TB is critical to reduce TB-related death. Recently-introduced interferon gamma release assay (IGRA) has better specificity than tuberculin skin test (TST) in TB screening and now become the standard for the identification of Mtb sensitization 1. Nevertheless, IGRA does not differentiate between active TB and resolved/latent infection 3. At present, sputum smear or culture of Mtb is still a gold standard for diagnosis of active TB. In addition, sputum culture is also a major biomarker for the evaluation of treatment 1,4,5. However, sputum test is assessable only when sputa of good quality were obtained from patients. Accordingly, sputum test is unavailable for infants with TB and patients with extrapulmonary tuberculosis. In addition, sputum test is not always available in resource-poor settings. Moreover, the sputum culture is not suitable for rapid decision making during therapy of outpatients, given that it requires long time before obtaining results 1. To detect Mtb in sputa in a rapid turnaround time, molecular diagnostics such as the GeneXpert MTB/RIF assay may be applicable 5. Nevertheless, this assay is ex...

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Plasma Leucine-Rich α-2-Glycoprotein 1 Predicts Rapid eGFR Decline and Albuminuria Progression in Type 2 Diabetes Mellitus

Abstract: Plasma LRG1 predicts both albuminuria and CKD progression beyond traditional risk factors. It may play a role in the pathologic pathway leading to progression of DKD in T2DM.

Cited by 51 publications

References 36 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

Plasma Leucine-Rich α-2-Glycoprotein 1 Predicts Cardiovascular Disease Risk in End-Stage Renal Disease

Leucine-rich alpha 2 glycoprotein is a new marker for active disease of tuberculosis

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