Over-expression of platelet-derived growth factor in human diabetic nephropathy

Langham, Robyn G; Kelly, Darren J.; Maguire, Julie; Dowling, John P.; Gilbert, Richard E.; Thomson, Napier M.

doi:10.1093/ndt/gfg177

Cited by 54 publications

(50 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…PDGF has been reported to inhibit adipocyte differentiation (19). In other organs, local PDGF has been suggested to play a role in pathogenesis of proliferative retinopathy and diabetic nephropathy (14,26,39). An increase in PDGF has been found in the retinal membranes and vitreous fluid of patients with proliferative diabetic retinopathy (14,39).…”

Section: Discussionmentioning

confidence: 99%

Macrophage infiltration into adipose tissue may promote angiogenesis for adipose tissue remodeling in obesity

Pang

Gao²,

Yin³

et al. 2008

American Journal of Physiology-Endocrinology and Metabolism

191

147

View full text Add to dashboard Cite

The biological role of macrophage infiltration into adipose tissue in obesity remains to be fully understood. We hypothesize that macrophages may act to stimulate angiogenesis in the adipose tissue. This possibility was examined by determining macrophage expression of angiogenic factor PDGF (platelet-derived growth factor) and regulation of tube formation of endothelial cells by PDGF. The data suggest that endothelial cell density was reduced in the adipose tissue of ob/ob mice. Expression of endothelial marker CD31 was decreased in protein and mRNA. The reduction was associated with an increase in macrophage infiltration. In the obese mice, PDGF concentration was elevated in the plasma, and its mRNA expression was increased in adipose tissue. Macrophages were found to be a major source of PDGF in adipose tissue, as deletion of macrophages led to a significant reduction in PDGF mRNA. In cell culture, PDGF expression was induced by hypoxia, and tube formation of endothelial cells was induced by PDGF. The PDGF activity was dependent on S6K, as inhibition of S6K in endothelial cells led to inhibition of the PDGF activity. We conclude that, in response to the reduced vascular density, macrophages may express PDGF in adipose tissue to facilitate capillary formation in obesity. Although the PDGF level is elevated in adipose tissue, its activity in angiogenesis is dependent on the availability of sufficient endothelial cells. The study suggests a new function of macrophages in the adipose tissue in obesity.

show abstract

Section: Discussionmentioning

confidence: 99%

Macrophage infiltration into adipose tissue may promote angiogenesis for adipose tissue remodeling in obesity

Pang

Gao²,

Yin³

et al. 2008

American Journal of Physiology-Endocrinology and Metabolism

191

147

View full text Add to dashboard Cite

show abstract

“…It has been known for a long time that PDGF is a necessary factor for the normal development of mesangial cells and that knockout mice for PDGF-B receptor lack mesangial cells (39). During diabetes, hyperglycemia is associated with glomerular upregulation of PDGF-B receptor (22,35) and its activation is likely involved in the progressive development of fibrosis via activation of the TGF-␤1 pathway (22).…”

Section: Discussionmentioning

confidence: 99%

ACE inhibitor reduces growth factor receptor expression and signaling but also albuminuria through B2-kinin glomerular receptor activation in diabetic rats

Allard¹,

Buléon²,

Cellier³

et al. 2007

American Journal of Physiology-Renal Physiology

View full text Add to dashboard Cite

Tack I, Girolami J-P. ACE inhibitor reduces growth factor receptor expression and signaling but also albuminuria through B2-kinin glomerular receptor activation in diabetic rats. Am J Physiol Renal Physiol 293: F1083-F1092, 2007. First published June 27, 2007; doi:10.1152/ajprenal.00401.2006 is associated with increased oxidative stress, overexpression and activation of growth factor receptors, including those for transforming growth factor-␤1 (TGF-␤-RII), platelet-derived growth factor (PDGF-R), and insulin-like growth factor (IGF1-R). These pathways are believed to represent pathophysiological determinants of DN. Beyond perfect glycemic control, angiotensin-converting enzyme inhibitors (ACEI) are the most efficient treatment to delay glomerulosclerosis. Since their mechanisms of action remain uncertain, we investigated the effect of ACEI on the glomerular expression of these growth factor pathways in a model of streptozotocin-induced diabetes in rats. The early phase of diabetes was found to be associated with an increase in glomerular expression of IGF1-R, PDGF-R, and TGF-␤-RII and activation of IRS1, Erk 1/2, and Smad 2/3. These changes were significantly reduced by ACEI treatment. Furthermore, ACEI stimulated glutathione peroxidase activity, suggesting a protective role against oxidative stress. ACEI decreased ANG II production but also increased bradykinin bioavailability by reducing its degradation. Thus the involvement of the bradykinin pathway was investigated using coadministration of HOE-140, a highly specific nonpeptidic B2-kinin receptor antagonist. Almost all the previously described effects of ACEI were abolished by HOE-140, as was the increase in glutathione peroxidase activity. Moreover, the well-established ability of ACEI to reduce albuminuria was also prevented by HOE-140. Taken together, these data demonstrate that, in the early phase of diabetes, ACEI reverse glomerular overexpression and activation of some critical growth factor pathways and increase protection against oxidative stress and that these effects involve B2-kinin receptor activation.angiotensin-converting enzyme inhibitor; oxidative stress; glutathione peroxidase activity; diabetes DIABETIC NEPHROPATHY (DN) causes the majority of end-stage renal diseases throughout the world (54). It was initially believed that elevated blood glucose was the major cause of renal damage in both type 1 and 2 diabetes. However, several clinical studies have demonstrated that strict glycemic control is not sufficient to prevent the progression of renal dysfunction and the development of glomerular lesions. The mechanisms underlying the progression of diabetic kidney disease are intricate and still not completely understood. Among the many pathophysiological mechanisms possible, several growth factors and cytokines have been put forward to account for the onset of DN. This is particularly the case for the paracrine expression of insulin-like growth factor-1 (IGF-1), transforming growth factor-␤ (TGF-␤) (20), and platelet-derived growth factor (PDG...

show abstract

“…In humans, PDGFs have been shown to be upregulated in glomerulosclerosis, as well as in diabetic and allograft-related nephropathies (Langham et al, 2003; Eitner et al, 2003), and PDGF inhibitors can inhibit pathogenic mesenchymal proliferation in the kidney (Savikko et al, 2003). PDGFA and PDGFB are also upregulated in human patients with diabetic proliferative retinopathy (Freyberger et al, 2000), and PDGF inhibition using a dominant-negative PDGFRα can inhibit the progression of proliferative vitreoretinopathy in an ex vivo model (Ikuno and Kazlauskas, 2002).…”

Section: Pdgfs and Human Diseasementioning

confidence: 99%

Roles of PDGF in animal development

2003

View full text Add to dashboard Cite

Platelet-derived growth factor (PDGF) was first identified in a search for serum factors that stimulate the proliferation of arterial smooth muscle cells (Ross et al., 1974). Since then, mammalian PDGFs have been extensively characterized in culture-based assays, where they have been shown to drive cellular responses including proliferation, survival, migration, and the deposition of extracellular matrix (ECM) and tissue remodeling factors. Knockout studies have demonstrated that many of these cellular responses to PDGFs are essential during mouse development. The genes that encode two ligands, Pdgfa and Pdgfb, and both receptors, PDGF receptor alpha and PDGF receptor beta (Pdgfra, Pdgfrb), have been knocked out in the mouse. These studies have demonstrated that PDGFB and PDGFRβ are essential for the development of support cells in the vasculature, whereas PDGFA and PDGFRα are more broadly required during embryogenesis, with essential roles in numerous contexts, including central nervous system, neural crest and organ development (Levéen et al., 1994;Soriano, 1994;Boström et al., 1996;Soriano, 1997; Fruttiger et al., 1999;Karlsson et al., 1999; Gnessi et al., 2000;Karlsson et al., 2000). Because of the severe and pleiotropic phenotypes of Pdgfa and Pdgfra knockout mouse embryos, many primary functions of PDGFs remained elusive until being addressed in experiments using conditional gene ablation and gain-offunction transgenics. Pdgfr signaling mutants have also been generated in which specific tyrosine residues in the receptor cytoplasmic domains have been mutated to phenylalanines. These mutations disrupt the interactions of PDGFRs with individual cytoplasmic signaling proteins and, in some cases, abrogate a subset of receptor functions (Heuchel et al., 1999;Tallquist et al., 2000;Klinghoffer et al., 2002) (M. Tallquist and P.S., unpublished). Together, such in vivo studies have demonstrated that the PDGFs perform distinct cellular roles at successive stages of mouse embryogenesis. In many contexts, PDGFs are mitogenic during early developmental stages, driving the proliferation of undifferentiated mesenchyme and some progenitor populations (reviewed by Betsholtz et al., 2001). During later maturation stages, PDGF signaling has been implicated in tissue remodeling and cellular differentiation, and in inductive events involved in patterning and morphogenesis. In mouse and Drosophila, PDGFs also direct cell migration, both at short and long distances from signal sources.This review discusses the known roles of PDGFs in development, with emphasis on cellular responses to PDGFs and how they contribute to neural/oligodendrocyte development, vascular and hematopoietic development, neural crest cell development, organogenesis, somitogenesis and skeletal patterning. Although most published studies of PDGF functions in vivo have been performed in mouse, early studies of PDGF-and PDGFR-related proteins in other model organisms suggest that some known PDGF roles (e.g. in glial/neural development) are conserved from fly ...

show abstract

Over-expression of platelet-derived growth factor in human diabetic nephropathy

Abstract: The findings of increased gene and protein expression of PDGF in renal biopsies from patients with diabetic nephropathy imply a potential role for this prosclerotic growth factor in the development of the progressive fibrosis that characterizes human diabetic kidney disease.

Cited by 54 publications

References 20 publications

Macrophage infiltration into adipose tissue may promote angiogenesis for adipose tissue remodeling in obesity

Macrophage infiltration into adipose tissue may promote angiogenesis for adipose tissue remodeling in obesity

ACE inhibitor reduces growth factor receptor expression and signaling but also albuminuria through B2-kinin glomerular receptor activation in diabetic rats

Roles of PDGF in animal development

Contact Info

Product

Resources

About