Decorin is significantly overexpressed in nephrogenic systemic fibrosis.
ABSTRACT The role of the proteoglycans in the pathogenesis of nephrogenic systemic fibrosis (NSF) is unclear. We assessed expression of decorin, versican, and transforming growth factor beta1 (TGF-beta1) in skin specimens of 10 patients with biopsy-proven NSF and different control groups. Real-time reverse transcription-polymerase chain reaction studies and immunohistochemical analysis were performed on full-thickness skin specimens. The messenger RNA (mRNA) and protein levels of decorin were significantly higher in the skin lesions of patients with NSF than in skin lesions of patients with systemic sclerosis, patients undergoing hemodialysis, and healthy subjects. The versican mRNA levels in NSF lesions differed significantly only from the levels in healthy subjects. TGF-beta1 mRNA expression was significantly overexpressed in NSF lesions compared with control skin specimens investigated. In NSF specimens, the mRNA expression of TGF-beta1 and decorin were highly correlated (r = 0.92). Our results suggest that decorin and TGF-beta1 may have a fundamental role in the pathogenesis of NSF. Conversely, versican seems less likely to be of pathogenetic significance in NSF.
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ABSTRACT: Nephrogenic systemic fibrosis (NSF) is a rare and a debilitating disease noted uncommonly in patients with impaired renal function when exposed to low-stability gadolinium-based contrast agents (Gd-CAs). According to experimental studies, cytokines released by the stimulation of effector cells such as skin macrophages and peripheral blood monocytes activate circulating fibroblasts which play a major role in the development of NSF lesions. The presence of permissive factors, presumably, provides an environment conducive to facilitate the process of fibrosis. Multiple treatment modalities have been tried with variable success rates. More research is necessary to elucidate the underlying pathophysiological mechanisms which could potentially target the initial steps of fibrosis in these patients. This paper attempts to collate the inferences from the in vivo and in vitro experiments to the clinical observations to understand the pathogenesis of NSF. Schematic representations of receptor-mediated molecular pathways of activation of macrophages and fibroblasts by gadolinium and the final pathway to fibrosis are incorporated in the discussion.International journal of nephrology. 01/2012; 2012:912189.
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ABSTRACT: Chronic renal inflammation is often associated with a progressive accumulation of various extracellular matrix constituents, including several members of the small leucine-rich proteoglycan (SLRP) gene family. It is becoming increasingly evident that the matrix-unbound SLRPs strongly regulate the progression of inflammation and fibrosis. Soluble SLRPs are generated either via partial proteolytic processing of collagenous matrices or by de novo synthesis evoked by stress or injury. Liberated SLRPs can then bind to and activate Toll-like receptors, thus modulating downstream inflammatory signaling. Preclinical animal models and human studies have recently identified soluble biglycan as a key initiator and regulator of various inflammatory renal diseases. Biglycan, generated by activated macrophages, can enter the circulation and its elevated levels in plasma and renal parenchyma correlate with unfavorable renal function and outcome. In this review, we will focus on the critical role of soluble biglycan in inflammatory signaling in various renal disorders. Moreover, we will provide new data implicating proinflammatory effects of soluble decorin in unilateral ureteral obstruction. Finally, we will critically evaluate the potential application of soluble biglycan vis-à-vis other SLRPs (decorin, lumican and fibromodulin) as a promising target and novel biomarker of inflammatory renal diseases.The international journal of biochemistry & cell biology. 08/2014;
Article: Nephrogenic systemic fibrosis.[Show abstract] [Hide abstract]
ABSTRACT: Nephrogenic systemic fibrosis (NSF) is a relatively new fibrosing disorder which has caught the attention of various specialities in the past decade. NSF is an extremely disabling and often painful condition, affecting up to 13% of the individuals with chronic kidney disease. The administration of a gadolinium chelate contrast agent has been reported to induce the development of NSF, particularly in patients who have acute or chronic renal disease with a glomerular filtration rate (GFR) lower than 30-mL/min/1.73 m(2) and in those with acute renal insufficiency. Mass spectroscopy studies have demonstrated particles of gadolinium in the lesional tissue. The exact pathogenesis of this curious sclerosing condition is unknown. The role of the aberrant targeting of 'circulating fibrocytes' to the peripheral tissues and viscera has been hypothesized. NSF has distinct clinicopathological features in the setting of renal failure and needs to be looked upon as a new entity on the block. The condition is characterized by irregular indurated plaques, with amoeba-like projections and islands of sparing, chiefly on the trunk and extremities. Flexion contractures of fingers, knees, and elbow joints are known to occur in advanced cases of NSF. The course is frequently associated with painful episodes and loss of ambulation. Histopathology shows haphazard arrangement of thickened bundles of collagen, varying amount of mucin, and increased population of fibroblast-like cells in the dermis. Immunohistochemistry shows increased deposition of type-I procollagen and CD 34+ cells having fibroblastic activity. The condition is refractory to treatment with corticosteroids and immunosuppressive agents. Various modalities of therapy such as UVA1 phototherapy, imatinib mesylate, photodynamic therapy, plasmapheresis, extracorporeal photochemotherapy, and high-dose intravenous immunoglobulin have shown a moderate degree of improvement in skin thickness scores. A prudent option is restoration of renal function to normalcy via renal transplantation but to date the outcome of renal transplantation is unknown.Indian dermatology online journal. 07/2011; 2(2):51-6.