Investigation of calmodulin and basic fibroblast growth factor (bFGF) in idiopathic myelofibrosis: evidence for a role of extracellular calmodulin in fibroblast proliferation

Dalley, Andrew J.; Smith, Joseph M.; Reilly, J; Neil, S. Mac

doi:10.1046/j.1365-2141.1996.d01-1739.x

Cited by 40 publications

(18 citation statements)

References 24 publications

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“…Our data were consistent with the data reported by Rastaldi et al (32) that renal tubular epithelial cells can produce ECM proteins and directly intervene in fibrotic processes via the epithelial-mesenchymal transdifferentiation. The increase in expression of a myofibroblast protein (fibroblast tropomyosin) and proteins associated with proliferation, modulation, and differentiation of myofibroblast and fibrogenesis (calmodulin and cellular retinol-binding protein; Table 2) provides further support for this process (33,34). In addition, Figure 6F shows a marked increase of elastin staining in the tubulointerstitium of an end-stage diabetic kidney.…”

Section: Discussionmentioning

confidence: 81%

Alterations in the Renal Elastin-Elastase System in Type 1 Diabetic Nephropathy Identified by Proteomic Analysis

Thongboonkerd¹,

Barati²,

McLeish

et al. 2004

Journal of the American Society of Nephrology

101

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Abstract. Diabetes now accounts for Ͼ40% of patients with ESRD. Despite significant progress in understanding diabetic nephropathy, the cellular mechanisms that lead to diabetesinduced renal damage are incompletely defined. For defining changes in protein expression that accompany diabetic nephropathy, the renal proteome of 120-d-old OVE26 transgenic mice with hypoinsulinemia, hyperglycemia, hyperlipidemia, and proteinuria were compared with those of background FVB nondiabetic mice (n ϭ 5). Proteins derived from whole-kidney lysate were separated by two-dimensional PAGE and identified by matrix-assisted laser desorption ionization-time-of-flight (MALDI-TOF) mass spectrometry. Forty-one proteins from 300 visualized protein spots were differentially expressed in diabetic kidneys. Among these altered proteins, expression of monocyte/neutrophil elastase inhibitor was increased, whereas elastase IIIB was decreased, leading to the hypothesis that elastin expression would be increased in diabetic kidneys. Renal immunohistochemistry for elastin of 325-d-old FVB and OVE26 mice demonstrated marked accumulation of elastin in the macula densa, collecting ducts, and pelvicalyceal epithelia of diabetic kidneys. Elastin immunohistochemistry of human renal biopsies from patients with type 1 diabetes (n ϭ 3) showed increased elastin expression in renal tubular cells and the interstitium but not glomeruli. These results suggest that coordinated changes in elastase inhibitor and elastase expression result in increased tubulointerstitial deposition of elastin in diabetic nephropathy. The identification of these coordinated changes in protein expression in diabetic nephropathy indicates the potential value of proteomic analysis in defining pathophysiology.Diabetes now accounts for Ͼ40% of patients with ESRD, and the number of renal failure patients with diabetes is expected to increase in the coming years (1). Renal pathologic changes that lead to decreased renal function are observed in all intrarenal structures, including glomeruli, tubulointerstitium, and blood vessels (2, 3). These morphologic changes, coupled with elevated intraglomerular pressure and hormonal dysregulation, lead to glomerulosclerosis, interstitial fibrosis, and ultimately renal failure (4, 5). Despite recent progress in understanding diabetic nephropathy, the cellular mechanisms that lead to diabetes-induced renal damage are incompletely defined.Recently, Clarkson et al. (6) demonstrated that at least 200 genes were differentially expressed in mesangial cells after exposure to high-glucose media. These findings indicate the complexity of the development of diabetic nephropathy. However, proteins, not genes, govern cellular functions. The study of changes in renal protein expression is necessary to understand better the complex pathogenic mechanisms of diabetic nephropathy. Conventional protein studies-Western blotting and other immunologic methods-are limited to a relatively small number of proteins that can be studied in each experiment and to previously ide...

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Section: Discussionmentioning

confidence: 81%

Alterations in the Renal Elastin-Elastase System in Type 1 Diabetic Nephropathy Identified by Proteomic Analysis

Thongboonkerd¹,

Barati²,

McLeish

et al. 2004

Journal of the American Society of Nephrology

101

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“…The elevated urinary bFGF levels reported by Dalley et al (1996), and bFGF levels that we bFGF in Patients with Idiopathic Myelofibrosis ᭧ 1997 Blackwell Science Ltd, British Journal of Haematology 97: [441][442][443][444][445][446][447][448] detected in the serum from some patients, could result from the abnormal release or leakage from dysplastic and necrotic megakaryocytic and/or platelets. In bone marrow, bFGF is bound to extracellular matrix and basement membrane heparan sulphate proteoglycans (Moscatelli, 1988) and the prolonged release of high amounts of sequestrated bFGF, should act in different ways, participating in the development of the disease.…”

Section: Discussionmentioning

confidence: 99%

Elevated levels of basic fibroblast growth factor in megakaryocytes and platelets from patients with idiopathic myelofibrosis

et al. 1997

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Idiopathic myelofibrosis, or agnogenic myeloid metaplasia, is a chronic myeloproliferative disorder characterized by clonal expansion and marrow fibrosis. Although marrow fibrosis appears to be a reactive process, it substantially contributes to impaired haemopoiesis. During the last few years the implication of megakaryocyte‐derived growth factors in its pathogenesis has been documented. We previously reported increased expression of TGF‐β in patients with idiopathic myelofibrosis. In the present study we show that circulating megakaryocytic cells from such patients expressed high levels of basic fibroblast growth factor (bFGF). An increased expression of bFGF was also detected in patients’ platelets. Under culture conditions, bFGF present in megakaryocytic cells was not exported into the medium, consistent with the fact that bFGF is devoid of a secretion peptide signal. Interestingly, this lack of bFGF secretion was observed in all patients but one, who was in an accelerated phase of the disease and presented an important percentage of circulating megakaryoblasts.

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“…19 In addition, several studies have reported that patients affected by MMM have increased circulating levels of TGF-␤ (trasforming growth factor-beta) and bFGF (basic fibroblast growth factor) that, beside other activities, are strong inducers of angiogenesis. [20][21][22] On this basis, we have evaluated the circulating serum concentrations of VEGF in a cohort of patients affected by MMM and we have found that most of them had levels much higher than control subjects, thus confirming the increase of angiogenesis in MMM.…”

Section: Introductionmentioning

confidence: 99%

Elevated vascular endothelial growth factor (VEGF) serum levels in idiopathic myelofibrosis

et al. 2001

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An increase of angiogenesis has been shown in idiopatic myelofibrosis with myeloid metaplasia (MMM) by microvessel density count method but evaluation of circulating angiogenic factors is still incomplete. In 31 patients affected by MMM and in 12 healthy subjects we evaluated the serum levels of VEGF (vascular endothelial growth factor) and correlated VEGF with clinical and laboratory features of disease. We found that MMM patients had circulating VEGF concentrations much higher than controls (median 1208 ng/ml vs 138 ng/ml, P Ͻ 0.0001). No correlation was found between VEGF and Hb, WBC, PLT, LDH, creatinine, bone marrow cellularity, fibrosis, splenomegaly, hepatomegaly, and therapy. However, in the subgroup of patients with a normal or low VEGF concentration, a direct correlation between VEGF and platelet count (r = 0.90, P = 0.002) was detected. Moreover, patients with a platelet count Ͻ300 × 10 9 /l had VEGF serum levels lower than patients with a higher PLT count (median VEGF 864 vs 1557 pg/ml, P = 0.001). In six patients and in eight controls we also had the opportunity to measure VEGF in the plasma and we calculated that VEGF concentration was much higher in platelet-rich than in platelet-poor plasma and that platetets of MMM patients contained four times more VEGF than those of healthy controls. These results indicate that VEGF is overproduced in MMM, thus confirming an increased angiogenic activity. Platelets are probably a major source of VEGF in MMM but not the only one. Leukemia (2001) 15, 976-980.

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Investigation of calmodulin and basic fibroblast growth factor (bFGF) in idiopathic myelofibrosis: evidence for a role of extracellular calmodulin in fibroblast proliferation

Cited by 40 publications

References 24 publications

Alterations in the Renal Elastin-Elastase System in Type 1 Diabetic Nephropathy Identified by Proteomic Analysis

Alterations in the Renal Elastin-Elastase System in Type 1 Diabetic Nephropathy Identified by Proteomic Analysis

Elevated levels of basic fibroblast growth factor in megakaryocytes and platelets from patients with idiopathic myelofibrosis

Elevated vascular endothelial growth factor (VEGF) serum levels in idiopathic myelofibrosis

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