Expression and localization of insulin‐like growth factor binding proteins in normal and proteinuric kidney glomeruli

Fujinaka, Hidehiko; Katsuyama, Koichi; Yamamoto, Keiko; Nameta, Masaaki; Yoshida, Yutaka; Yaoita, Eishin; Tomizawa, Shuichi; Yamamoto, Tadashi

doi:10.1111/j.1440-1797.2010.01285.x

Cited by 24 publications

(24 citation statements)

References 30 publications

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“…Interestingly, animal model studies have demonstrated the increased expression of IGFBP-2 in the glomerulus in anti-glomerular basement membrane (GBM) glomerulonephritis in the rat [42] and Murphy Roths Large lymphoproliferation (MRL/ lpr) lupus mice [46]. In human immunoglobulin (Ig)A nephropathy, glomerular expression levels of IGFBP-2 mRNA were increased significantly compared to normal glomeruli [42]. Of relevance to our study, IGFBP-2 has also been reported to be increased in nephrotic syndrome in paediatric patients [19] and as a predictor of longitudinal deterioration of renal function in type 2 diabetes [20].…”

Section: Discussionmentioning

confidence: 99%

Insulin-like growth factor binding protein-2 as a novel biomarker for disease activity and renal pathology changes in lupus nephritis

Ding

Kharboutli

Saxena

et al. 2016

Clinical and Experimental Immunology

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SummaryLupus nephritis (LN) is one of the most serious manifestations of systemic lupus erythematosus. Invasive renal biopsy remains the gold standard for the diagnosis and management of LN. The objective of this study is to validate serum insulin-like growth factor binding protein-2 (IGFBP-2) as a novel biomarker for clinical disease and renal pathology in LN. Eighty-five biopsyproven lupus nephritis patients, 18 chronic kidney disease (CKD) patients and 20 healthy controls were recruited for enzyme-linked immunosorbent assay (ELISA) testing of serum IGFBP-2 levels. Compared to CKD patients of origins other than lupus or healthy controls, serum IGFBP-2 levels were elevated significantly in LN patients. Serum IGFBP-2 was able to discriminate LN patients from the other two groups of patients [area under the curve (AUC) 5 0Á65, 95% confidence interval (CI) 5 0Á52-0Á78; P 5 0Á043 for LN versus CKD; 0Á97, 95% CI 5 0Á93-1Á00; P < 0Á0001 for LN versus healthy controls]. Serum IGFBP-2 was a potential indicator of both global disease activity and renal disease activity in LN patients, correlated with serum creatinine levels (r 5 0Á658, P < 0Á001, n 5 85) and urine protein-to-creatinine levels (r 5 0Á397, P < 0Á001, n 5 85). More importantly, in 19 concurrent patient samples, serum IGFBP-2 correlated with the chronicity index of renal pathology (r 5 0Á576, P 5 0Á01, n 5 19) but not renal pathological classification. In conclusion, serum IGFBP-2 is a promising biomarker for lupus nephritis, reflective of disease activity and chronicity changes in renal pathology.

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Section: Discussionmentioning

confidence: 99%

Insulin-like growth factor binding protein-2 as a novel biomarker for disease activity and renal pathology changes in lupus nephritis

Ding

Kharboutli

Saxena

et al. 2016

Clinical and Experimental Immunology

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“…It is the second most prevalent serum IGFBP, and has been reported to be a good biomarker of several malignancies . Interestingly, glomerular IGFBP‐2 expression has been reported to be increased in animal models of anti–glomerular basement membrane glomerulonephritis and MRL/lpr lupus . IGFBP‐2 has also been documented to be raised in patients with diabetic nephropathy .…”

Section: Discussionmentioning

confidence: 99%

Axl, Ferritin, Insulin‐Like Growth Factor Binding Protein 2, and Tumor Necrosis Factor Receptor Type II as Biomarkers in Systemic Lupus Erythematosus

Mok

Ding

Kharboutli

et al. 2016

Arthritis Care & Research

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Objective-To evaluate the performance of 4 serum protein markers for detecting concurrent clinical activity in patients with systemic lupus erythematosus (SLE).Methods-Consecutive patients who fulfilled ≥4 ACR criteria for SLE and healthy controls were recruited for serological testing of 4 protein markers identified by antibody-coated microarray screen, namely Axl, ferritin, IGFBP2 and TNFR2. SLE disease activity was assessed by the SELENA-SLEDAI and physician's global assessment (PGA). Levels of these markers were correlated with SLEDAI and their sensitivity and specificity for clinical SLE activity was determined.Results-A total of 94 SLE patients (98% women; age 28.7±9.4 years, disease duration 5.4±5.0 years) and 49 healthy controls were studied. Fifty-two patients had clinically active SLE (SLEDAI score ≥6 or having a flare). The serum concentrations of Axl, ferritin, IGFBP2 and TNFR2 were significantly higher in patients with active SLE than inactive SLE or controls. The levels of these markers correlated strongly and significantly with anti-dsDNA, C3, clinical SLEDAI and PGA scores. These markers were more specific, but less sensitive, in detecting concurrent SLE activity than elevated anti-dsDNA or depressed C3. Levels of Axl, TNFR2 and IGFBP2, but not ferritin, could differentiate active renal from active non-renal or inactive SLE. The specificity of Axl and IGFBP2 for concurrent active lupus nephritis was higher than anti-dsDNA or C3. Contributions to this work:Chi Chiu 1b, 1c,2, 1b,2,1b,2, 1b,2,3 HHS Public Access Author Manuscript Author ManuscriptAuthor Manuscript Author ManuscriptConclusions-Serum proteomic markers are potentially useful for diagnosing SLE and monitoring disease activity. The performance of Axl and IGFBP2 in lupus nephritis should be further explored in a longitudinal cohort of SLE patients.

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“…Initial work focused on the mesangial cell [19], showing that this cell produces IGF-I, expresses the IGF-IR and that local IGF-I signalling may be increased in a number of disease states, including diabetes [20]. Recently it has been recognized that the podocyte is also an important source [22] and target [23] of IGF-I, and that IGFs are important for podocyte and glomerular development [24]. Our work has confirmed that IGF-I is produced in the glomerulus and that the podocyte is the major source of this hormone here.…”

Section: Discussionmentioning

confidence: 99%

Insulin‐like growth factor‐II is produced by, signals to and is an important survival factor for the mature podocyte in man and mouse

Hale

Welsh²,

Perks³

et al. 2013

The Journal of Pathology

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Podocytes are crucial for preventing the passage of albumin into the urine and, when lost, are associated with the development of albuminuria, renal failure and cardiovascular disease. Podocytes have limited capacity to regenerate, therefore pro-survival mechanisms are critically important. Insulin-like growth factor-II (IGF-II) is a potent survival and growth factor; however, its major function is thought to be in prenatal development, when circulating levels are high. IGF-II has only previously been reported to continue to be expressed in discrete regions of the brain into adulthood in rodents, with systemic levels being undetectable. Using conditionally immortalized human and ex vivo adult mouse cells of the glomerulus, we demonstrated the podocyte to be the major glomerular source and target of IGF-II; it signals to this cell via the IGF-I receptor via the PI3 kinase and MAPK pathways. Functionally, a reduction in IGF signalling causes podocyte cell death in vitro and glomerular disease in vivo in an aged IGF-II transgenic mouse that produces approximately 60% of IGF-II due to a lack of the P2 promoter of this gene. Collectively, this work reveals the fundamental importance of IGF-II in the mature podocyte for glomerular health across mammalian species.

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Expression and localization of insulin‐like growth factor binding proteins in normal and proteinuric kidney glomeruli

Abstract: IGFBP-2, -7, -8 and -10 are produced by normal and injured glomerular podocytes and may regulate local IGF-I actions in podocytes and/or cortical tubular cells in the kidney.

Cited by 24 publications

References 30 publications

Insulin-like growth factor binding protein-2 as a novel biomarker for disease activity and renal pathology changes in lupus nephritis

Insulin-like growth factor binding protein-2 as a novel biomarker for disease activity and renal pathology changes in lupus nephritis

Axl, Ferritin, Insulin‐Like Growth Factor Binding Protein 2, and Tumor Necrosis Factor Receptor Type II as Biomarkers in Systemic Lupus Erythematosus

Insulin‐like growth factor‐II is produced by, signals to and is an important survival factor for the mature podocyte in man and mouse

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