RESUMO
Chronic kidney disease (CKD) is a serious health problem worldwide, which ultimately leads to end-stage renal disease (ESRD). Renal fibrosis is the common pathway and major pathological manifestation for various CKD proceeding to ESRD. However, the underlying mechanisms and effective therapies are still ambiguous. Early growth response 2 (EGR2) is reportedly involved in organ formation and cell differentiation. To determine the role of EGR2 in renal fibrosis, we respectively confirmed the increased expression of EGR2 in kidney specimens from both CKD patients and mice with location in proximal tubules. Genetic deletion of EGR2 attenuated obstructive nephropathy while EGR2 overexpression further promoted renal fibrosis in mice subjected to unilateral ureteral obstruction (UUO) due to extracellular matrix (ECM) deposition mediating by partial epithelial-mesenchymal transition (EMT) as well as imbalance between matrix metalloproteinases (MMPs) and tissue inhibitor of MMPs (TIMPs). We found that EGR2 played a critical role in Smad3 phosphorylation, and inhibition of EGR2 reduced partial EMT leading to blockade of ECM accumulation in cultured human kidney 2 cells (HK2) treated with transforming growth factor ß1 (TGF-ß1). In addition, the transcription co-stimulator signal transducer and activator of transcription 3 (STAT3) phosphorylation was confirmed to regulate the transcription level of EGR2 in TGF-ß1-induced HK2 cells. In conclusion, this study demonstrated that EGR2 played a pathogenic role in renal fibrosis by a p-STAT3-EGR2-p-Smad3 axis. Thus, targeting EGR2 could be a promising strategy for CKD treatment.
Assuntos
Transição Epitelial-Mesenquimal , Fibrose , Proteína Smad3 , Animais , Humanos , Masculino , Camundongos , Linhagem Celular , Matriz Extracelular/metabolismo , Matriz Extracelular/patologia , Rim/patologia , Rim/metabolismo , Camundongos Endogâmicos C57BL , Fosforilação , Insuficiência Renal Crônica/patologia , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/genética , Proteína Smad3/metabolismo , Proteína Smad3/genética , Obstrução Ureteral/patologia , Obstrução Ureteral/complicações , Obstrução Ureteral/metabolismoRESUMO
Hypoxia has long been considered to play an active role in the progression of fibrosis in chronic kidney disease, but its specific mechanism is not fully understood. The stimulator of interferon genes (STING) has been a research hotspot in the fields of tumor, immunity, and infection in recent years, and its role in immune and inflammatory responses related to kidney disease has gradually attracted attention. This study mainly explores the role and mechanism of STING in hypoxia-related renal fibrosis. To address this issue, we stimulated human proximal tubular epithelial (HK-2) cells with hypoxia for 48 h to construct cell models. Meanwhile, C57BL/6J male mice were used to establish a renal fibrosis model induced by renal ischemia-reperfusion injury (IRI). In our present study, we found that the GMP-AMP synthase (cGAS)-STING signaling pathway can promote the progression of renal fibrosis after hypoxic exposure, and this effect is closely related to 6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase 3 (PFKFB3)-mediated glycolysis. Furthermore, inhibition of both STING and its downstream interferon regulatory factor 3 (IRF3) reversed elevated PFKFB3 expression, thereby attenuating hypoxia-induced renal fibrosis. Taken together, our data suggest that the cGAS-STING-IRF3-PFKFB3 signaling pathway activated under hypoxia may provide new ideas and targets for the treatment of early renal fibrosis.
Assuntos
Nefropatias , Fosfofrutoquinase-2 , Animais , Humanos , Masculino , Camundongos , Fibrose/metabolismo , Glicólise , Hipóxia/metabolismo , Nefropatias/metabolismo , Camundongos Endogâmicos C57BL , Nucleotidiltransferases/genética , Nucleotidiltransferases/metabolismo , Fosfofrutoquinase-2/genética , Fosfofrutoquinase-2/metabolismo , Transdução de SinaisRESUMO
Diabetic kidney disease (DKD) accounts for a large proportion of end-stage renal diseases that require renal replacement therapies including dialysis and transplantation. Therefore, it is critical to understand the occurrence and development of DKD. Podocytes are mainly injured during the development of DKD, ultimately leading to their extensive death and loss. In turn, the injury and death of glomerular podocytes are also the main culprits of DKD. This review introduces the characteristics of podocytes and summarizes the modes of their death in DKD, including apoptosis, autophagy, mitotic catastrophe (MC), anoikis, necroptosis, and pyroptosis. Apoptosis is characterized by nuclear condensation and the formation of apoptotic bodies, and it exerts a different effect from autophagy in mediating DKD-induced podocyte loss. MC mediates a faulty mitotic process while anoikis separates podocytes from the basement membrane. Moreover, pyroptosis activates inflammatory factors to aggravate podocyte injuries whilst necroptosis drives signaling cascades, such as receptor-interacting protein kinases 1 and 3 and mixed lineage kinase domain-like, ultimately promoting the death of podocytes. In conclusion, a thorough knowledge of the modes of podocyte death in DKD can help us understand the development of DKD and lay the foundation for strategies in DKD disease therapy.
Assuntos
Diabetes Mellitus , Nefropatias Diabéticas , Podócitos , Apoptose , Autofagia , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/metabolismo , Humanos , Transdução de SinaisRESUMO
BACKGROUND: In the present study, we aimed to investigate the effects of probucol on aging-related hippocampus-dependent cognitive impairment and explore the potential mechanisms. METHODS: D-galactose (100 mg/kg, once daily for 6 weeks) was subcutaneously injected to induce aging in mice. Then the mice were administered with probucol or vehicle once a day for 2 weeks. The hippocampus-related cognition was evaluated with Morris water maze test, novel object recognition test, and contextual fear conditioning test. Moreover, synaptic plasticity was assessed, and RNA-sequencing was applied to further explore the molecular mechanisms. RESULTS: Aging mice induced by D-galactose showed conspicuous learning and memory impairment, which was significantly ameliorated by probucol. Meanwhile, probucol enhanced the spine density and dendritic branches, improved long-term potentiation, and increased the expression of PSD95 of aging mice. Probucol regulated 70 differentially expressed genes compared to D-galactose group, of which 38 genes were upregulated and 32 genes were downregulated. At last, RNA-sequencing results were verified by quantitative reverse transcription-polymerase chain reaction. CONCLUSIONS: Probucol improved learning and memory in aging mice through enhancing synaptic plasticity and regulating gene expression, indicating the potential application of probucol to prevent and treat aging-related disorders.
Assuntos
Comportamento Animal/efeitos dos fármacos , Cognição/efeitos dos fármacos , Disfunção Cognitiva/tratamento farmacológico , Hipocampo/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Nootrópicos/farmacologia , Probucol/farmacologia , Fatores Etários , Animais , Senescência Celular/efeitos dos fármacos , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/fisiopatologia , Disfunção Cognitiva/psicologia , Inibidor p16 de Quinase Dependente de Ciclina/genética , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Modelos Animais de Doenças , Proteína 4 Homóloga a Disks-Large/metabolismo , Medo/efeitos dos fármacos , Regulação da Expressão Gênica , Hipocampo/metabolismo , Hipocampo/patologia , Hipocampo/fisiopatologia , Potenciação de Longa Duração/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Teste do Labirinto Aquático de Morris/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Teste de Campo Aberto/efeitos dos fármacos , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismoRESUMO
BACKGROUND: Chemokines are a family of proteins mainly mediating the homing and migration of various cells. The CXC chemokine CXCL12 is a member of low-weight-molecular chemokines. In the kidney, CXCL12 is pivotal for renal development and exerts a modulatory effect in kidney diseases under different etiologic settings by binding with CXC chemokine receptor 4 (CXCR4) or CXC chemokine receptor 7 (CXCR7). Besides, CXCL12 also exerts homeostasis influence in diverse physical conditions and various pathological situations. Thus, we conclude the complicated relationship between CXCL12 and kidney diseases in this review. SUMMARY: In renal development, CXCL12 contributes a lot to nephrogenesis and the formation of renal vasculature via correlating with CXCR4. CXCL12 also plays an essential role in renal recovery from acute kidney injury. However, the CXCL12/CXCR4 axis plays a dual regulatory role in the initiation and development of diabetic kidney disease as well as chronic allogeneic nephropathy after kidney transplantation through dialectical consideration. Additionally, the CXCL12/CXCR4 link is considered as a new risk factor for lupus nephritis and renal cell carcinoma. KEY MESSAGES: Plenty of studies have presented the influence of CXCL12 and the relation with corresponding receptors in diverse biological and pathological statuses. Simultaneously, some drugs and antagonists targeting CXCL12/CXCR4 axis effectively treat various kidney diseases. However, more researches are needed to explore thorough influence and mechanisms, providing more cues for clinical treatments.
RESUMO
Various well-designed nanostructures have been proposed to optimize the electrode systems of lithium-ion batteries for problems like Li(+) diffusion, electron transport, and large volume changes so as to fulfill effective capacity utilization and increase electrode stability. Here, a novel three-dimensional (3D) hybrid Sn-Ni@PEO nanotube array is synthesized as a high performance anode for a lithium-ion battery through a simple one-step electrodeposition for the first time. Superior to the traditional stepwise synthesis processes of heterostructured nanomaterials, this one-step method is more suitable for practical applications. The electrode morphology is well preserved after repeated Li(+) insertion and extraction, indicating that the positive synergistic effect of the alloy nanotube array and 3D ultrathin PEO coating could authentically optimize the current volume-expansion electrode system. The electrochemistry results further confirm that the superiority of the Sn-Ni@PEO nanotube array electrode could largely boost durable high reversible capacities and superior rate performances compared to a Sn-Ni nanowire array. This proposed ternary hybrid structure is proven to be an ideal candidate for the development of high performance anodes for lithium-ion batteries.