scholarly journals Aminoguanidine Ameliorates Overexpression of Prosclerotic Growth Factors and Collagen Deposition in Experimental Diabetic Nephropathy

2001 ◽  
Vol 12 (10) ◽  
pp. 2098-2107 ◽  
Author(s):  
DARREN J. KELLY ◽  
RICHARD E. GILBERT ◽  
ALISON J. COX ◽  
TINA SOULIS ◽  
GEORGE JERUMS ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Growth Factors ◽  
Growth Factor ◽  
Experimental Diabetes ◽  
Fold Increase ◽  
Diabetic Rats ◽  
Renal Tubules ◽  
Collagen Deposition ◽  
Matrix Deposition ◽  
Tgf Β1

Abstract. Profibrotic cytokines and the formation of advanced-glycation end products (AGE) have both been implicated in the pathogenesis of glomerulosclerosis in diabetic kidney disease. However, tubulointerstitial pathology is also an important determinant of progressive renal dysfunction in diabetic nephropathy. This study sought to investigate the expression of profibrotic growth factors and matrix deposition in the glomerulus and the tubulointerstitium and to examine the effect of blocking AGE formation in experimental diabetic nephropathy. Thirty-six male Sprague-Dawley rats were randomized into control and diabetic groups. Diabetes was induced in 24 rats by streptozotocin. Twelve diabetic rats were further randomized to receive the inhibitor of AGE formation, aminoguanidine (1 g/l drinking water). At 6 mo, experimental diabetes was associated with a three-fold increase in expression of transforming growth factor (TGF)-β1 (P< 0.01versuscontrol) and five-fold increase in platelet-derived growth factor (PDGF)-B gene expression (P< 0.01versuscontrol) in the tubulointerstitium.In situhybridization demonstrated a diffuse increase in both TGF-β1 and PDGF-B mRNA in renal tubules. Aminoguanidine attenuated not only the overexpression of TGF-β1 and PDGF-B but also reduced type IV collagen deposition in diabetic rats (P< 0.05). TGF-β1 and PDGF mRNA within glomeruli were also similarly increased with diabetes and attenuated with aminoguanidine. The observed beneficial effects of aminoguanidine on the tubulointerstitium in experimental diabetes suggest that AGE-mediated expression of profibrotic cytokines may contribute to tubulointerstitial injury and the pathogenesis of diabetic nephropathy.

scholarly journals Streptozocin Diabetes Elevates all Isoforms of TGF-β in the Rat Kidney

2001 ◽  
Vol 2 (1) ◽  
pp. 55-62 ◽  
Author(s):  
Pascale H. Lane ◽  
Dustin M. Snelling ◽  
William J. Langer
Keyword(s):  
Diabetic Nephropathy ◽  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Rat Kidney ◽  
Fold Increase ◽  
Diabetic Rat ◽  
The Impact ◽  
Tgf Β1

Transforming growth factor beta (TGF-β) is a major promoter of diabetic nephropathy. While TGF-β1 is the most abundaft renal isoform, types 2 and 3 are present as well and have identicalin vitroeffects. Whole kidney extracts were studied 2 weeks after induction of streptozocin diabetes and in control rats. Mean glomerular area was 25% greater in the diabetic animals. TGF-β1 showed a 2-fold increase in message with a 3-fold increase in protein. TGF-β2 mRNA increased approximately 6% while its protein doubled. TGF-β-message increased by 25%, producing a 35% increase in its protein. TGF-β- inducible gene H3 mRNA was increased 35% in the diabetic animals, consistent with increased activity of this growth factor. All isoforms of TGF-β are increased in the diabetic rat kidney. Future studies need to address the specific role that each isoform plays in diabetic nephropathy as well as the impact of therapies on each isoform.

TGF-β1-induced PAI-1 gene expression requires MEK activity and cell-to-substrate adhesion

2001 ◽  
Vol 114 (21) ◽  
pp. 3905-3914 ◽  
Author(s):  
Stacie M. Kutz ◽  
John Hordines ◽  
Paula J. McKeown-Longo ◽  
Paul J. Higgins
Keyword(s):  
Cell Migration ◽  
Growth Factors ◽  
Growth Factor ◽  
Cell Motility ◽  
Target Genes ◽  
Combined Treatment ◽  
Cell System ◽  
Matrix Deposition ◽  
Tgf Β1 ◽  
Pai 1

The type-1 inhibitor of plasminogen activator (PAI-1) is an important physiological regulator of extracellular matrix (ECM) homeostasis and cell motility. Various growth factors mediate temporal changes in the expression and/or focalization of PAI-1 and its protease target PAs, thereby influencing cell migration by barrier proteolysis and/or ECM adhesion modulation. TGF-β1, in particular, is an effective inducer of matrix deposition/turnover, cell locomotion and PAI-1 expression. Therefore, the relationship between motility and PAI-1 induction was assessed in TGF-β1-sensitive T2 renal epithelial cells. PAI-1 synthesis and its matrix deposition in response to TGF-β1 correlated with a significant increase in cell motility. PAI-1 expression was an important aspect in cellular movement as PAI-1-deficient cells had significantly impaired basal locomotion and were unresponsive to TGF-β1. However, the induced migratory response to this growth factor was complex. TGF-β1 concentrations of 1-2 ng/ml were significantly promigratory, whereas lower levels (0.2-0.6 ng/ml) were ineffective and final concentrations ≥5 ng/ml inhibited T2 cell motility. This same growth factor range progressively increased PAI-1 transcript levels in T2 cells consistent with a bifunctional role for PAI-1 in cell migration. TGF-β1 induced PAI-1 mRNA transcripts in quiescent T2 cells via an immediate-early response mechanism. Full TGF-β1-stimulated expression required tyrosine kinase activity and involved MAPK/ERK kinase (MEK). MEK appeared to be a major mediator of TGF-β1-dependent PAI-1 expression and T2 cell motility since PD98059 effectively attenuated both TGF-β1-induced ERK1/2 activation and PAI-1 transcription as well as basal and growth factor-stimulated planar migration. Since MEK activation in response to growth factors is adhesion-dependent, it was important to determine whether cellular adhesive state influenced TGF-β1-mediated PAI-1 expression in the T2 cell system. Cells maintained in suspension culture (i.e., over agarose underlays) in growth factor-free medium or treated with TGF-β1 in suspension expressed relatively low levels of PAI-1 transcripts compared with the significant induction of PAI-1 mRNA evident in T2 cells upon stimulation with TGF-β1 during adhesion to a fibronectin-coated substrate. Attachment to fibronectin alone (i.e., in the absence of added growth factor) was sufficient to initiate PAI-1 transcription, albeit at levels considerably lower than that induced by the combination of cell adhesion in the presence of TGF-β1. T2 cells allowed to attach to vitronectin-coated surfaces also expressed PAI-1 transcripts but to a significantly reduced extent relative to cells adherent to fibronectin. Moreover, newly vitronectin-attached cells did not exhibit a PAI-1 inductive response to TGF-β1, at least during the short 2 hour period of combined treatment. PAI-1 mRNA synthesis in response to substrate attachment, like TGF-β1-mediated induction in adherent cultures, also required MEK activity as fibronectin-stimulated PAI-1 expression was effectively attenuated by the MEK inhibitor PD98059. These data indicate that cellular adhesive state modulates TGF-β1 signaling to particular target genes (i.e., PAI-1) and that MEK is a critical mediator of the PAI-1+/promigratory phenotype switch induced by TGF-β1 in T2 cells.

scholarly journals Long-term effects of local growth factor (IGF-I and TGF-β1) treatment on fracture healing. A safety study for using growth factors

2004 ◽  
Vol 22 (3) ◽  
pp. 514-519 ◽  
Author(s):  
Gerhard Schmidmaier ◽  
Britt Wildemann ◽  
Daniel Ostapowicz ◽  
Frank Kandziora ◽  
Richard Stange ◽  
...  
Keyword(s):  
Growth Factors ◽  
Growth Factor ◽  
Fracture Healing ◽  
Long Term Effects ◽  
Local Growth ◽  
Safety Study ◽  
Igf I ◽  
Tgf Β1

Platelet-Rich Plasma Powder: A New Preparation Method for the Standardization of Growth Factor Concentrations

2016 ◽  
Vol 45 (4) ◽  
pp. 954-960 ◽  
Author(s):  
Matthias Kieb ◽  
Frank Sander ◽  
Cornelia Prinz ◽  
Stefanie Adam ◽  
Anett Mau-Möller ◽  
...  
Keyword(s):  
Growth Factors ◽  
Growth Factor ◽  
Clinical Application ◽  
Whole Blood ◽  
Sports Medicine ◽  
Transforming Growth Factor ◽  
Platelet Rich Plasma ◽  
Transforming Growth Factor Β1 ◽  
Enzyme Linked Immunosorbent Assay ◽  
Tgf Β1

Background: Platelet-rich plasma (PRP) is widely used in sports medicine. Available PRP preparations differ in white blood cell, platelet, and growth factor concentrations, making standardized research and clinical application challenging. Purpose: To characterize a newly standardized procedure for pooled PRP that provides defined growth factor concentrations. Study Design: Controlled laboratory study. Methods: A standardized growth factor preparation (lyophilized PRP powder) was prepared using 12 pooled platelet concentrates (PCs) derived from different donors via apheresis. Blood samples and commercially available PRP (SmartPrep-2) served as controls (n = 5). Baseline blood counts were analyzed. Additionally, single PCs (n = 5) were produced by standard platelet apheresis. The concentrations of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), platelet-derived growth factor AB (PDGF-AB), transforming growth factor β1 (TGF-β1), insulin-like growth factor 1 (IGF-1), interleukin (IL)–1α, IL-1β, and IL-1 receptor agonist (IL-1RA) were analyzed by enzyme-linked immunosorbent assay, and statistical analyses were performed using descriptive statistics, mean differences, 95% CIs, and P values (analysis of variance). Results: All growth factor preparation methods showed elevated concentrations of the growth factors VEGF, bFGF, PDGF-AB, and TGF-β1 compared with those of whole blood. Large interindividual differences were found in VEGF and bFGF concentrations. Respective values (mean ± SD in pg/mL) for whole blood, SmartPrep-2, PC, and PRP powder were as follows: VEGF (574 ± 147, 528 ± 233, 1087 ± 535, and 1722), bFGF (198 ± 164, 410 ± 259, 151 ± 99, and 542), PDGF-AB (2394 ± 451, 17,846 ± 3087, 18,461 ± 4455, and 23,023), and TGF-β1 (14,356 ± 4527, 77,533 ± 13,918, 68,582 ± 7388, and 87,495). IGF-1 was found in SmartPrep-2 (1539 ± 348 pg/mL). For PC (2266 ± 485 pg/mL), IGF-1 was measured at the same levels of whole blood (2317 ± 711 pg/mL) but was not detectable in PRP powder. IL-1α was detectable in whole blood (111 ± 35 pg/mL) and SmartPrep-2 (119 ± 44 pg/mL). Conclusion: Problems with PRP such as absent standardization, lack of consistency among studies, and black box dosage could be solved by using characterized PRP powder made by pooling and lyophilizing multiple PCs. The new PRP powder opens up new possibilities for PRP research as well as for the treatment of patients. Clinical Relevance: The preparation of pooled PRP by means of lyophilization may allow physicians to apply a defined amount of growth factors by using a defined amount of PRP powder. Moreover, PRP powder as a dry substance with no need for centrifugation could become ubiquitously available, thus saving time and staff resources in clinical practice. However, before transferring the results of this basic science study to clinical application, regulatory issues have to be cleared.

scholarly journals Protective Effects of Luteolin on Diabetic Nephropathy in STZ-Induced Diabetic Rats

2011 ◽  
Vol 2011 ◽  
pp. 1-7 ◽  
Author(s):  
Guo Guang Wang ◽  
Xiao Hua Lu ◽  
Wei Li ◽  
Xue Zhao ◽  
Cui Zhang
Keyword(s):  
Diabetic Nephropathy ◽  
Growth Factor ◽  
High Glucose ◽  
Transforming Growth Factor ◽  
Antioxidant Properties ◽  
Diabetic Rats ◽  
Heme Oxygenase 1 ◽  
Protective Effects ◽  
Sod Activity ◽  
Matrix Expression

Diabetic nephropathy is a long-term complication of diabetic mellitus. Many experimental evidences suggest that persistent hyperglycaemia generates intracellular reactive oxygen species (ROS) and upregulates transforming growth factor-b1 and extracellular matrix expression in mesangial and tubular epithelial cells, which is involved of free radicals in the pathogenesis of diabetes and more importantly in the development of diabetic complications. Antioxidants effectively inhibit high-glucose- and H2O2-induced transforming growth factor-b1 and fibronectin upregulation, thus providing evidence that ROS play an important role in high glucose-induced renal injury. The flavonoid luteolin has been shown to possess direct antioxidant activity, therefore we hypothesize that it may be useful in treatment of many chronic disease associated with oxidative stress, such as diabetic nephropathy via its antioxidant properties. Our results suggested that protection against development of diabetic nephropathy by luteolin treatment involved changes in superoxide dismutase (SOD) activity, the malondialdehyde (MDA) content and expression of Heme Oxygenase-1 (HO-1) protein.

Kidney tissue insulin-like growth factor I and initial renal growth in diabetic rats: Relation to severity of diabetes

1990 ◽  
Vol 122 (3) ◽  
pp. 374-378 ◽  
Author(s):  
Allan Flyvbjerg ◽  
Hans Ørskov
Keyword(s):  
Blood Glucose ◽  
Growth Factor ◽  
Experimental Diabetes ◽  
Diabetic Rats ◽  
Renal Hypertrophy ◽  
Kidney Weight ◽  
Factor I ◽  
Urinary Glucose ◽  
Igf I ◽  
Growth Factor I

Abstract The initial renal hypertrophy in experimental diabetes is dependent on the prevailing blood glucose level and is associated with renal accumulation of insulinlike growth factor I. To investigate the relationship of blood glucose to kidney IGF-I, a graded range of diabetic aberration was established in young rats by iv injection of increasing amounts of streptozotocin (25–80 mg/kg) at day 0. In 30 diabetic rats the mean of day 1 and day 2 blood glucose concentrations ranged from 6.2 to 32.0 mmol/l and 24-h urinary glucose excretion (24–48 h) from 0.04 to 43.3 mmol/24 h. The right kidneys were removed after 48 h, weighed and their IGF-I concentration analysed by radioimmunoassay. Kidney IGF-I was positively correlated to blood glucose (r = 0.66, p<0.0001) as well as to 24-h urinary glucose output (r = 0.54, p<0.005). At this early stage, kidney weight already correlated to blood glucose (r = 0.60, p<0.0005). No relationship between kidney IGF-I and kidney weight was found. However, if animals with severe diabetes were excluded, a significant correlation could be established (r = 0.51, p = 0.01, N = 24). The results support the hypothesis that IGF-I plays a causal role in the initial renal hypertrophy of experimental diabetes.

Effects of Aspirin on Growth Factor Release From Freshly Isolated Leukocyte-Rich Platelet-Rich Plasma in Healthy Men: A Prospective Fixed-Sequence Controlled Laboratory Study

2019 ◽  
Vol 47 (5) ◽  
pp. 1223-1229 ◽  
Author(s):  
Prathap Jayaram ◽  
Peter Yeh ◽  
Shiv J. Patel ◽  
Racel Cela ◽  
Theodore B. Shybut ◽  
...  
Keyword(s):  
Growth Factors ◽  
Growth Factor ◽  
Whole Blood ◽  
Low Dose ◽  
Platelet Rich Plasma ◽  
Healthy Men ◽  
Growth Factor Release ◽  
Tgf Β1 ◽  
Cox 1 ◽  
Factor Release

Background: The benefits of platelet-rich plasma (PRP) are believed to be in part dependent on growth factor release after platelet activation. Platelet activation is complex and involves multiple mechanisms. One important mechanism is driven by cyclooxygenase 1 (COX-1)–mediated conversion of arachidonic acid (AA) to precursor prostaglandins that then mediate proinflammatory responses that trigger growth factor release. Acetylsalicylic acid (ASA; also known as aspirin) is known to irreversibly inhibit COX-1, thereby blocking AA-mediated signaling; however, it is unclear whether ASA use alters growth factor release from freshly isolated PRP. Purpose: To assess the effects of low-dose ASA use on activation of growth factor release from freshly isolated human PRP via AA and thrombin (TBN). Study Design: Controlled laboratory study. Methods: Twelve healthy men underwent blood collection and leukocyte-rich PRP (LR-PRP) preparation through a double-spin protocol to obtain baseline whole blood and PRP counts the same day. PRP was aliquoted into 3 groups: nonactivated, AA activated, and TBN activated. Immediately after activation, the concentrations of transforming growth factor β1 (TGF-β1), vascular endothelial growth factor (VEGF), and platelet-derived growth factor AB (PDGF-AB) were measured using enzyme-linked immunosorbent assays (ELISAs). The same 12 participants were then placed on an 81-mg daily dose of oral ASA for 14 days. Repeat characterization of whole blood and PRP analyses was done on day 14, followed by repeat ELISAs of growth factors under the same nonactivated and activated settings as previously stated. Results: Fourteen days of daily ASA had no effect on the number of platelets and leukocytes measured in whole blood and LR-PRP. Compared with nonactivated LR-PRP, AA- and TBN-mediated activation led to significant release of VEGF and PDGF-AB. In contrast, release of TGF-β1 from LR-PRP was observed only with activation by AA, not with TBN. Consistent with its inhibitory role in AA signaling, ASA significantly inhibited AA-mediated release of all 3 growth factors measured in this study. Although ASA had no effect on TBN-mediated release of VEGF and TGF-β1 from LR-PRP, ASA did partially block TBN-mediated release of PDGF-AB, although the mechanism remains unclear. Conclusion: Daily use of low-dose ASA reduces VEGF, PDGF-AB, and TGF-β1 expression in freshly isolated human LR-PRP when activated with AA. Clinical Relevance: Reduction in growth factor release attributed to daily use of low-dose ASA or other COX inhibitors can be mitigated when PRP samples are activated with TBN. Clinical studies are needed to determine whether activation before PRP injection is needed in all applications where ASA is in use and to what extent ASA may inhibit growth factor release in vivo at the site of injury.

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