endothelin-1 and Cicatrix

Fibrotic diseases are a significant global burden for which there are limited treatment options. The effector cells of fibrosis are activated fibroblasts called myofibroblasts, a highly contractile cell type characterized by the appearance of α-smooth muscle actin stress fibers. The underlying mechanism behind myofibroblast differentiation and persistence has been under much investigation and is known to involve a complex signaling network involving transforming growth factor-β, endothelin-1, angiotensin II, CCN2 (connective tissue growth factor), and platelet-derived growth factor. This review addresses the contribution of these signaling molecules to cardiac fibrosis.

Topics: Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Animals; Anti-Inflammatory Agents; Arrhythmias, Cardiac; Atrophy; Cicatrix; Connective Tissue Growth Factor; Endothelin Receptor Antagonists; Endothelin-1; Fibrosis; Humans; Hypoxia; Models, Cardiovascular; Molecular Targeted Therapy; Myocardium; Myofibroblasts; Platelet-Derived Growth Factor; Pyridones; Rats; Signal Transduction; Transforming Growth Factor beta

Endothelin-1 (ET-1) contributes to renal fibrogenesis in several manners such as increasing collagen synthesis in mesangium, decreasing extracellular matrix (ECM) degradation by mesangial cells and stimulating mesangial contraction. The aim of our study was to investigate whether urine level of ET-1 (uET-1) could represent a useful biomarker of renal scarring and if so, to determine the optimal cutoff level for uET-1 to predict a renal scar.. 44 children with renal scarring and 32 children without renal scarring were enrolled in the study. Urine ET-1 was measured by enzyme-linked immunosorbent assay.. Mean uET-1 level was significantly higher in the scar group than in controls (2.75 ± 1.35 fmol/ml vs. 0.68 ± 0.41 fmol/ml, p = 0.001). The optimal cut-off level was 1.064 fmol/ml for uET-1 to predict renal scarring. Using this cut-off point, sensitivity and specificity were 97.73% and 93.91%, respectively. AUC was found 0.975 (95% CI 0.917 - 0.996) for uET-1. Mean urine Endothelin-1/Creatinine ratio (uET-1/Cr) was also significantly higher in the scar group than in the control group (4.04 ± 2.29 fmol/mg Cr vs. 1.09 ± 0.67 fmol/mg Cr, p = 0.0001). Using 1.67 fmol/mgCr as optimal cut-off level, sensitivity and specificity were 95.45% and 84.09%, respectively. AUC was 0.945 (95% CI 0.875 - 0.982) for uET-1/Cr.. Our study suggests that both uET-1 and uET-1/Cr can be used for prediction of renal scarring in children with normal renal function. Measuring urine level of ET-1 can help us to avoid unnecessary DMSA studies if the patient's uET-1 level is found to be under the determined cut-off point.

Topics: Adolescent; Age Factors; Biomarkers; Case-Control Studies; Child; Child, Preschool; Cicatrix; Creatinine; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Female; Fibrosis; Glomerular Filtration Rate; Humans; Kidney; Male; Predictive Value of Tests; Prospective Studies; Sensitivity and Specificity; Turkey; Up-Regulation; Urinary Tract Infections

Glycogen synthase kinase-3 (GSK-3) is a widely expressed and highly conserved serine/threonine protein kinase encoded by 2 genes, GSK3A and GSK3B. GSK-3 is thought to be involved in tissue repair and fibrogenesis, but its role in these processes is currently unknown. To investigate the function of GSK-3beta in fibroblasts, we generated mice harboring a fibroblast-specific deletion of Gsk3b and evaluated their wound-healing and fibrogenic responses. We have shown that Gsk3b-conditional-KO mice (Gsk3b-CKO mice) exhibited accelerated wound closure, increased fibrogenesis, and excessive scarring compared with control mice. In addition, Gsk3b-CKO mice showed elevated collagen production, decreased cell apoptosis, elevated levels of profibrotic alpha-SMA, and increased myofibroblast formation during wound healing. In cultured Gsk3b-CKO fibroblasts, adhesion, spreading, migration, and contraction were enhanced. Both Gsk3b-CKO mice and fibroblasts showed elevated expression and production of endothelin-1 (ET-1) compared with control mice and cells. Antagonizing ET-1 reversed the phenotype of Gsk3b-CKO fibroblasts and mice. Thus, GSK-3beta appears to control the progression of wound healing and fibrosis by modulating ET-1 levels. These results suggest that targeting the GSK-3beta pathway or ET-1 may be of benefit in controlling tissue repair and fibrogenic responses in vivo.

Topics: Animals; Apoptosis; beta Catenin; Bosentan; Cell Line; Cicatrix; Collagen; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Female; Fibroblasts; Fibrosis; Gene Expression Regulation; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Receptor, Endothelin A; Receptor, Endothelin B; Sequence Deletion; Signal Transduction; Sulfonamides; Time Factors; Wound Healing