Biomedical subjects

Stavros Topouzis

Publications and source records attributed to Stavros Topouzis.

5 recordsLinked to original sources

PubMed2004

Myostatin signaling through Smad2, Smad3 and Smad4 is regulated by the inhibitory Smad7 by a negative feedback mechanism.

As a member of the TGF-beta superfamily, myostatin is a specific negative regulator of skeletal muscle mass. To identify the downstream components in the myostatin signal transduction pathway, we used a luciferase reporter assay to elucidate myostatin-induced activity. The myostatin-induced transcription requires the participation of regulatory Smads (Smad2/3) and Co-Smads (Smad4). Conversely, inhibitory Smad7, but not Smad6, dramatically reduces the myostatin-induced transcription. This Smad7 inhibition is enhanced by co-expression of Smurf1. We have also shown that Smad7 expression is stimulated by myostatin via the interaction between Smad2, Smad3, Smad4 and the SBE (Smad binding element) in the Smad7 promoter. These results suggest that the myostatin signal transduction pathway is regulated by Smad7 through a negative feedback mechanism.

Base Sequence↗

PubMed2004

Interleukin 31, a cytokine produced by activated T cells, induces dermatitis in mice.

T cell-derived cytokines are important in the development of an effective immune response, but when dysregulated they can promote disease. Here we identify a four-helix bundle cytokine we have called interleukin 31 (IL-31), which is preferentially produced by T helper type 2 cells. IL-31 signals through a receptor composed of IL-31 receptor A and oncostatin M receptor. Expression of IL-31 receptor A and oncostatin M receptor mRNA was induced in activated monocytes, whereas epithelial cells expressed both mRNAs constitutively. Transgenic mice overexpressing IL-31 developed severe pruritus, alopecia and skin lesions. Furthermore, IL-31 receptor expression was increased in diseased tissues derived from an animal model of airway hypersensitivity. These data indicate that IL-31 may be involved in promoting the dermatitis and epithelial responses that characterize allergic and non-allergic diseases.

Amino Acid Sequence↗

PubMed2004

Exogenous PDGF-D is a potent mesangial cell mitogen and causes a severe mesangial proliferative glomerulopathy.

The PDGF family consists of at least four members, PDGF-A, -B, -C, and -D. All of the PDGF isoforms bind and signal through two known receptors, PDGF receptor-alpha and PDGF receptor-beta, which are constitutively expressed in the kidney and are upregulated in specific diseases. It is well established that PDGF-B plays a pivotal role in the mediation of glomerular mesangial cell proliferation. However, little is known of the roles of the recently discovered PDGF-C and -D in mediating renal injury. In this study, adenovirus constructs encoding PDGF-B, -C, and -D were injected into mice. Mice with high circulating levels of PDGF-D developed a severe mesangial proliferative glomerulopathy, characterized by enlarged glomeruli and a striking increase in glomerular cellularity. The PDGF-B-overexpressing mice had a milder proliferative glomerulopathy, whereas the mice overexpressing PDGF-C and those that received adenovirus alone showed no measurable response. Mitogenicity of PDGF-D and -B for mesangial cells was confirmed in vitro. These findings emphasize the importance of engagement of PDGF receptor-beta in transducing mesangial cell proliferation and demonstrate that PDGF-D is a major mediator of mesangial cell proliferation. Finally, this approach has resulted in a unique and potentially valuable model of mesangial proliferative glomerulopathy and its resolution.

Animals↗

PubMed2003

Obstructive uropathy in mice and humans: potential role for PDGF-D in the progression of tubulointerstitial injury.

Tubulointerstitial fibrosis is a major characteristic of progressive renal diseases. Platelet-derived growth factor (PDGF) is a family of growth regulatory molecules consisting of PDGF-A and -B, along with the newly discovered PDGF-C and -D. They signal through cell membrane receptors, PDGF receptor alpha (PDGF-Ralpha) and receptor beta (PDGF-Rbeta). Involvement of PDGF-B and PDGF-Rbeta in the initiation and progression of renal fibrosis has been well documented. The authors studied the localization of PDGF ligands and receptors by immunohistochemistry, with emphasis on the role of PDGF-D in murine renal fibrosis induced by unilateral ureteral obstruction (UUO). In mice with UUO, de novo expression of PDGF-D was detected in interstitial cells at day 4, which increased to maximal expression at day 14. Increased expression of PDGF-B by interstitial cells and in some tubules was observed after day 4. The diseased mice did not show augmentation of PDGF-A or PDGF-C proteins in the areas of fibrosis. PDGF-Ralpha and -Rbeta protein expression was increased in interstitial cells after day 4 and reached maximal expression at day 14. Human renal nephrectomies (n = 10) of chronic obstructive nephropathy demonstrated similar de novo expression of PDGF-D in interstitial cells, correlating with expression of PDGF-Rbeta and PDGF-B, as it did in the murine model. These observations suggest that PDGF-D plays an important role in the pathogenesis of tubulointerstitial injury through binding of PDGF-Rbeta in both human obstructive nephropathy and the corresponding murine model of UUO.

Actins↗

PubMed2002

Platelet-derived growth factor-D expression in developing and mature human kidneys.

BACKGROUND: Platelet-derived growth factor (PDGF) is a family of growth regulatory molecules composed of sulfide-bonded dimeric structures. Two well-studied PDGF peptides (PDGF-A and PDGF-B) have been shown to mediate a wide range of biological effects. PDGF-D is a newly recognized member of the PDGF family. Initial studies of the PDGF-D gene found its expression in cells of the vascular wall, suggesting that it could participate in vascular development and pathology. However, its localization in human kidney tissues has never been studied. METHODS: PDGF-D expression in fetal (N = 30) and adult (N = 25) human kidney tissues was examined by immunohistochemistry using an affinity-purified antibody raised to human PDGF-D. Antibody absorption with the immunizing peptide was employed to confirm the specificity of this antibody. PDGF-D protein and gene expression in human kidneys also were demonstrated by Western blotting and reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: In the developing kidney, PDGF-D was first expressed by epithelial cells of comma- and S-shaped structures of the developing nephron, and most consistently in the visceral epithelial cells in the later stages of glomerular differentiation. In addition, PDGF-D could be found in mesenchymal, presumptively fibroblast cells in the interstitium of developing renal pelvis and in fetal smooth muscle cells in arterial vessels. In the adult normal kidney, PDGF-D was expressed by the visceral epithelial cells. There was persistent expression in arterial smooth muscle cells as well as in some neointimal smooth muscle cells of arteriosclerotic vessels, and expression in smooth muscle cells of vasa rectae in the medulla. PDGF-D could be identified at the basolateral membrane of some injured tubules in areas of chronic tubulointerstitial injury routinely encountered in aging kidneys. Western blotting of homogenates of adult kidneys demonstrated monospecific bands at 50 kD corresponding to previously established size parameter for this protein. RT-PCR of human kidney RNA resulted in a 918 basepair band, the sequence of which corresponded to human PDGF-D (Genbank number AF336376). CONCLUSIONS: To our knowledge, these are the first studies to localize PDGF-D in human kidneys and suggest that PDGF-D may have a role in kidney development. PDGF-D was shown to bind to PDGF beta receptor, which localizes to mesangial cells, parietal epithelial cells, and interstitial fibroblasts, suggesting potential paracrine interactions between those cells and the visceral epithelium.

Adult↗