Platelet-derived growth factor in experimental glomerulonephritis

Growth factors and in particular platelet-derived growth factor(PDGF) have been implicated in the pathogenesis of glomerulonephritisand glomerulosclerosis. We have studied the distribution ofimmunoreactive PDGF (iPDGF) within serial kidney biopsies (days7, 15, 30, 90 and 120) of eight rats with an accelerated formof nephrotoxic serum nephritis (NTN). The course of NTN wasmild in five rats and severe in three. Two patterns of immunostainfor PDGF were noted. The first consisted of iPDGF-B chain ina glomerular segmental distribution similar to that of infiltratingmonocytes (OX6+cells). At all stages of NTN the distributionof iPDGF-B chain correlated closely with the immunostain formonocytes. The second pattern of immunostain showed iPDGF-Achain in a diffuse distribution along the glomerular capillarylining and to a lesser extent in some mesangial cells. In severelyaffected rats the magnitude of the iPDGF-A increased along withglomerulosclerosis but disappeared later from areas of segmentaland global glomerular obsolescence. By contrast, in rats withmilder NTN glomerular iPDGF-A chain peaked early and decreasedsubsequently. During the acute phase of NTN, on day 7, iPDGFA chain correlated with the severity of proteinuria (r=0.848,P<0.05) and that of glomerular cellular proliferation (r=0.91,P<0.02). On day 30 iPDGF-B correlated positively with proteinuria(r=0.998, P<0.01, n=5) and with serum creatinine (r=0.949,P<0.02, n=5). During the late stages of NTN, both iPDGF-A(day 90, r=0.884, P<0.05) and iPDGF-B (day 120, r=0.941,P<0.01) correlated closely with the extent of glomerulosclerosis.Both PDGF chains (A and B) are detectable through out the courseof nephrotoxic nephritis in rats. PDGF may play a role in theearly proliferative and late sclerotic changes of experimentalglomerulonephritis.     

Platelet-derived growth factor in Dupuytren's disease.

This study investigated whether platelet-derived growth factor, a potent inducer of cell proliferation, was identifiable in association with myofibroblasts in Dupuytren's disease. Myofibroblasts in the hypercellular disease stages showed a strong reaction to platelet-derived growth factor antibody using light and electron microscopic immunochemical labels. Platelet-derived growth factor may play a role as a cellular signal for myofibroblast proliferation in the formation of the pathognomonic nodule in Dupuytren's disease.     

Platelet-derived growth factor and platelet profiles in childhood nephrotic syndrome

The aim of the study was to investigate (1) whether there are any changes in release of platelet-derived growth factor AA (PDGF AA) in children with nephrotic syndrome without clinical thromboembolic symptoms 2; (2) whether serum PDGF AA correlates with the platelet count (PLT) and platelet indices; (3) whether prednisone therapy affects the serum PDGF AA and the PLT; (4) whether PDGF AA is a useful predictor of disease activity. The study involved two groups of children: 33 with nephrotic syndrome (I) who were evaluated twice (A during relapse and B after 2 weeks of prednisone treatment) and 34 healthy children (II). The serum concentration of PDGF was measured by ELISA. In group I/A the PLT ( P <0.01) and platelet distribution width ( P <0.05) were elevated, the mean platelet volume (MPV) ( P <0.05) was decreased and the plateletcrit ( P >0.05) was normal. In group I/B, the PLT was decreased and MPV increased. The concentration of PDGF AA was still increased and correlated negatively with the albumin concentration. Hence in children with nephrotic syndrome an increase in PLT, a decrease in MPV, and a higher concentration of PDGF were observed. Treatment of nephrotic syndrome with prednisone for 2 weeks is not sufficient to normalize platelet parameters. Further studies are necessary to confirm the role of PDGF AA in the hypercoagulation state in children with nephrotic syndrome.     

大鼠心脏移植与动脉硬化

目的 探讨移植心脏的冠状动脉硬化的发生和发展。方法 以供体脾细胞（SPC）和环磷酰胺（CP）预处理移植受体,诱导受体对移植物的免疫耐受。在移植术后的不同时间,取出移植心脏,行Van Gieson染色,对移植心脏的冠状动脉硬化进行分析。结果 SPC和CP预处理后,移植心脏的存活时间明显延长,冠状动脉硬化明显减轻。结论 胶原纤维在血管壁内的广泛当浸润,是引起冠状动脉向心性狭窄的主要原因之一;SPC和CP预处理,可以预防和减缓移植心脏动脉硬化的发生和发展。     

Platelet-derived growth factor mesangial deposits in mesangial IgA glomerulonephritis

Platelets may play a role in the pathogenesis of IgA glomerulonephritis (IgAGN). Ultrastructural labelling of platelet antigens might identify activated platelets, and localisation of platelet antigens may assist in understanding the role of platelets in glomerular disease. We examined renal biopsies from eight patients with mesangial IgAGN using protein A-gold immunoelectron microscopy. Serial sections were stained with antisera against platelet-derived growth factor (PDGF), platelet factor 4, beta-thrombolglobulin, platelet glycoprotein IIb-IIIa complex, and fibrinogen, as well as antisera against IgA, IgG, IgM and C3c. Platelets, including activated and degranulated platelets, were detected in capillaries in five of eight biopsies. PDGF was detected in mesangial deposits in five of eight cases. In one case immunolabelling was as intense as IgA labelling. Fibrinogen labelling was present in six of eight. Less intense labelling or negative results were obtained with the other antisera. There was no correlation between intensity of immunolabelling and any clinical or morphological features reflecting severity of glomerular lesions. The role of platelets in the pathogenesis of IgAGN remains unclear. The documentation of frequent deposit of PDGF should stimulate further interest in PDGF participation in this condition.     

Platelet-derived growth factor receptors in the kidney--upregulated expression in inflammation

Major features of a long-standing inflammation in the kidney are vascular proliferation, glomerulosclerosis, interstitial fibrosis and tubular atrophy, leading to a gradual deterioration of the renal function. In this study we have investigated the expression of B-type receptors for platelet-derived growth factor (PDGF) in frozen sections from normal and inflamed kidneys. Immunohistochemical techniques, employing two monoclonal antibodies specific for PDGF B-type receptors, were used. The specimens investigated were 15 kidneys removed by transplantectomy because of chronic rejection, 20 cases of glomerulonephritis with crescent formation, mesangial proliferation or non-proliferative glomerulonephritis, and six normal kidneys. In parallel we characterized cellular infiltrates and class II transplantation antigen expression in the inflamed kidneys. An enhanced PDGF receptor expression was found on intimal cells and on smooth muscle cells of the proliferating vessels, on glomerular cells in glomeruli with mesangial proliferation, and on fibroblast-like cells in the proximity of clusters of infiltrating macrophages and T-lymphocytes of the interstitial tissue. Induction of PDGF receptor expression may render cells responsive to stimulation by PDGF, released from PDGF-producing cells, such as activated macrophages and from platelets. Our data suggest that PDGF is involved in the proliferation of mesenchymal cells that is seen in rejected kidney transplants and glomerulonephritis.     

Chronic allograft nephropathy is prevented by inhibition of platelet-derived growth factor receptor: tyrosine kinase inhibitors as a potential therapy

BACKGROUND: Chronic allograft nephropathy (CAN) is the primary reason for late allograft loss in kidney transplantation, and currently there is no treatment available for it. Platelet-derived growth factor (PDGF) is suggested to be a major mitogen mediating mesenchymal cell proliferation in CAN. It has been shown that PDGF is already induced at acute renal allograft rejection, indicating a link between acute rejection and subsequent development of CAN. However, the definite effect of PDGF on the pathogenesis of CAN is still unknown. We investigated the role of PDGF in CAN by inhibiting PDGF by imatinib (STI571), a selective PDGF receptor tyrosine kinase inhibitor. METHODS: Kidney transplantations were performed from Dark Agouti (DA) to Wistar-Furth rats, and syngenic control transplantations were performed from DA to DA rats. All allograft recipients were immunosuppressed with cyclosporine A (1.5 mg/kg/day subcutaneously). One group of the animals was also treated with imatinib (10 mg/kg/day orally). Serum creatinine levels and cyclosporine A concentrations were measured once per week until the animals were killed. Grafts were harvested 5 and 90 days after transplantation for histology and immunohistochemistry. RESULTS: Only very few histologic chronic changes, similar to syngenic grafts, were seen in imatinib-treated allografts compared with control allografts. Creatinine values of imatinib-treated allograft recipients and infiltration of inflammatory cells, PDGF ligand, and receptor induction were also at the same level as in syngenic grafts. CONCLUSIONS: Our results demonstrate that imatinib prevents CAN almost completely, indicating that PDGF plays an important role in its pathogenesis. On the basis of our findings, imatinib could be a potential intervention in preventing CAN in clinical kidney transplantation.     

Effect of platelet-activating factor (PAF) receptor blockers on smooth muscle cell replication in vitro and allograft arteriosclerosis in vivo

Platelet-activating factor (PAF) stimulates smooth muscle cell (SMC) replication both in vivo and in vitro. In this study we have investigated whether PAF receptor-blocking molecules modulate SMC replication in vitro and the generation of allograft arteriosclerosis in vivo. SMC cultures were established from baby rat aorta media and fibroblast control cultures from the adventitia. Identification of the cultured cell types was determined both by immunohistochemistry and electron microscopy. Both cell types replicated in culture with 10% fetal calf serum (FCS). The addition of PAF-C₁₈ enhanced, and the addition of three PAF receptor inhibitors — WEB 2086, WEB 2170, and BN 50739-reduced, SMC replication and protein synthesis in a dose-dependent fashion in vitro until toxic concentrations were reached. The most potent of these drugs, WEB 2170, was then delivered at the rate of 12 mg/kg per day to recipients of rat aortic allografts. The responses were quantitated by autoradiography after short-term labeling of the recipients with tritium-labeled thymidine (³H-TdR) and by quantitative morphology. Administration of the PAF receptor blocker had no impact on the replication of the inflammatory cells in the allograft adventitia nor on the replication of SMCs in the media and intima. Administration of the PAF receptor blocker delayed the generation of allograft arteriosclerosis slightly, but not significantly. These results suggest that PAF is not an essential component in the inflammatory cascade leading to allograft arteriosclerosis.     

血小板源性生长因子在肾脏疾病的研究进展

血小板源性生长因子(Platelet-derived growth factor,PDGF)系统,包含4个亚型(PDGF-A、B、C、D)和2个受体PDGFR-α、β.PDGF在绝大多数肾脏细胞都有表达,调节众多病理生理事件,如促进细胞DNA合成;诱导细胞进行有丝分裂;促进多种细胞外基质的积聚;产生抗炎因子和炎症介质前体;提高组织渗透性;调节血流动力学等.几乎只要有PDGF组成表达发生改变就会导致人类肾脏疾病.对PDGF的组成、信号转导、在肾脏的分布及表达、与肾脏疾病的关系等的研究具有重要意义.     

Platelet-derived growth factor and vascular endothelial growth factor expression in disc herniation tissue: an immunohistochemical study

Angiogenesis is essential in tissue growth and regeneration. There are several factors that are able to stimulate vascular endothelial cell growth, including platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF). Disc herniation tissue (DHT) contains vascular ingrowth, which promotes granulation tissue formation. In this study we observed 50 disc herniations for PDGF and VEGF immunoreactivity. PDGF immunopositivity was detected in 38 samples (78%). In 28 samples (56%) there were PDGF immunopositive capillaries, PDGF immunopositive disc cells were detected in 19 samples (38%) and PDGF immunopositive fibroblasts in 6 DHT samples (12%). VEGF immunopositive capillaries were identified in 44 DHT samples (88%). For neither growth factor was immunopositivity dependent on preoperative radicular pain duration. In extrusions (n = 25) VEGF immunopositive capillaries were detected in 23 samples (92%) and PDGF immunopositivity in 21 samples (84%). PDGF immunopositivity was more commonly associated with capillaries than with nuclei of disc cells. In sequesters (n = 20) VEGF immunopositive capillaries were identified in all samples and PDGF immunopositivity in 16 (80%). As in extrusions, PDGF immunoreaction was more prevalent in capillaries than in disc cells. Patient age did not relate to VEGF expression. In all age groups it was higher than 80%. Thus capillaries in disc herniation tissue are evidently newly formed and our results demonstrate that PDGF and VEGF participate in the neovascularization process. The presence of PDGF in fibroblasts and in disc cells suggests that this growth factor regulates the function of these cells, possibly the proliferation of the cells and the production of extracellular matrix components.