ABSTRACT
Diabetic nephropathy (DN) is an important factor leading to end-stage kidney disease that affects diabetes mellitus patients globally. Our previous transcriptome sequencing has identified a large group of differentially expressed long noncoding RNA (lncRNA) in early development of DN. On basis of this, we aimed to investigate the function of lncRNA NONHSAG053901 in DN pathogenesis. In this study, we revealed that the expression of NONHSAG053901 was drastically elevated in both DN mouse model and mesangial cells (MCs). It was found that overexpression of NONHSAG053901 remarkably promoted inflammation, fibrosis and proliferation in MCs. Consistently, further investigations suggested that the stimulation of NONHSAG053901 on proinflammatory cytokines via direct binding to early growth response protein 1 (Egr-1). Interaction between Egr-1 and transforming growth factor ß (TGF-ß) could augment TGF-ß function in DN inflammation. Furthermore, the effects of NONHSAG053901 on stimulation of proinflammatory cytokines were abolished by knockdown of Egr-1. These results together suggested that NONHSAG053901 promoted proinflammatory cytokines via stimulating Egr-1/TGF-ß mediated renal inflammation.
Subject(s)
Diabetic Nephropathies/genetics , Early Growth Response Protein 1/metabolism , Inflammation/genetics , Inflammation/pathology , Kidney/pathology , RNA, Long Noncoding/metabolism , Transforming Growth Factor beta/metabolism , Animals , Cell Proliferation/genetics , Cytokines/metabolism , Diabetic Nephropathies/pathology , Disease Models, Animal , Female , Fibrosis , Gene Expression Regulation , Inflammation Mediators/metabolism , Mesangial Cells/metabolism , Mesangial Cells/pathology , Mice , Protein Binding/genetics , RNA, Long Noncoding/genetics , StreptozocinABSTRACT
FGFR3 (fibroblast growth factor receptor 3) is a negative regulator of endochondral ossification. Gain-of-function mutations in FGFR3 are responsible for achondroplasia, the most common genetic form of dwarfism in humans. Autophagy, an evolutionarily conserved catabolic process, maintains chondrocyte viability in the growth plate under stress conditions, such as hypoxia and nutritional deficiencies. However, the role of autophagy and its underlying molecular mechanisms in achondroplasia remain elusive. In this study, we found activated FGFR3 signaling inhibited autophagic activity in chondrocytes, both in vivo and in vitro. By employing an embryonic bone culture system, we demonstrated that treatment with autophagy inhibitor 3-MA or chloroquine led to cartilage growth retardation, which mimics the effect of activated-FGFR3 signaling on chondrogenesis. Furthermore, we found that FGFR3 interacted with ATG12-ATG5 conjugate by binding to ATG5. More intriguingly, FGFR3 signaling was found to decrease the protein level of ATG12-ATG5 conjugate. Consistently, using in vitro chondrogenic differentiation assay system, we showed that the ATG12-ATG5 conjugate was essential for the viability and differentiation of chondrocytes. Transient transfection of ATG5 partially rescued FGFR3-mediated inhibition on chondrocyte viability and differentiation. Our findings reveal that FGFR3 inhibits the autophagic activity by decreasing the ATG12-ATG5 conjugate level, which may play an essential role in the pathogenesis of achondroplasia.
ABSTRACT
In forensic psychiatric evaluation, experts frequently need to assess the contribution degree of hurting factors to the victims. The contribution degree reflects the extent of hurt caused by the injurer and is the quantitative index of the responsibility which should be undertaken by the injurer. It is also important evidence for the judgement. Presently, there is no accepted and practicable quantitative tool to reflect the objective contribution degree. This article reviews domestic and international researches on the contribution degree of hurting factors in mental injury, including the concept, connotation, related assessment methods, problems in assessment and its future study trend.
