RESUMO
Renal fibrosis is the final pathological change in renal disease, and aging is closely related to renal fibrosis. Mitochondrial dysfunction has been reported to play an important role in aging, but the exact mechanism remains unclear. Disulfide-bond A oxidoreductase-like protein (DsbA-L) is mainly located in mitochondria and plays an important role in regulating mitochondrial function and endoplasmic reticulum (ER) stress. However, the role of DsbA-L in renal aging has not been reported. In this study, we showed a reduction in DsbA-L expression, the disruption of mitochondrial function and an increase in fibrosis in the kidneys of 12- and 24-month-old mice compared to young mice. Furthermore, the deterioration of mitochondrial dysfunction and fibrosis were observed in DsbA-L-/- mice with D-gal-induced accelerated aging. Transcriptome analysis revealed a decrease in Flt4 expression and inhibition of the PI3K-AKT signaling pathway in DsbA-L-/- mice compared to control mice. Accelerated renal aging could be alleviated by an AKT agonist (SC79) or a mitochondrial protector (MitoQ) in mice with D-gal-induced aging. In vitro, overexpression of DsbA-L in HK-2 cells restored the expression of Flt4, AKT pathway factors, SP1 and PGC-1α and alleviated mitochondrial damage and cell senescence. These beneficial effects were partially blocked by inhibiting Flt4. Finally, activating the AKT pathway or improving mitochondrial function with chemical reagents could alleviate cell senescence. Our results indicate that the DsbA-L/AKT/PGC-1α signaling pathway could be a therapeutic target for age-related renal fibrosis and is associated with mitochondrial dysfunction.
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Glutationa Transferase , Nefropatias , Rim , Mitocôndrias , Animais , Camundongos , Envelhecimento , Fibrose , Homeostase , Rim/patologia , Nefropatias/enzimologia , Mitocôndrias/enzimologia , Doenças Mitocondriais/enzimologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Glutationa Transferase/metabolismoRESUMO
Kidney injury is common in patients with Coronavirus Disease-19 (COVID-19), which is related to poor prognosis. We aim to summarize the clinical features, athological types, and prognosis of COVID-19 associated kidney injury caused by the Omicron strain. In this study, 46 patients with Omicron-associated kidney injury were included, 38 of whom performed renal biopsy. Patients were divided into two groups: group A for patients with onset of kidney injury after SARS-CoV-2 infection; group B for patients with pre-existing kidney disease who experienced aggravation of renal insufficiency after SARS-CoV-2 infection. The clinical, pathological, and prognostic characteristics of the patients were observed. Acute kidney injury (AKI) (35%) was the most common clinical manifestation in group A. Patients in group B mainly presented with chronic kidney disease (CKD) (55%) and nephrotic syndrome (NS) (40%). The pathological type was mainly IgA nephropathy (IgAN) (39% in group A and 45% in group B). Among all of them, one case presenting with thrombotic microangiopathy had worse kidney function at biopsy time. Mean serum C3 levels were 1.2 ± 0.5 and 1.0 ± 0.2 g/L in group A and group B, respectively. In renal tissues, C3 deposits were observed in 71.1% of patients. 11.8% (n = 2) patients experienced deterioration of renal function after treatment, but no patients developed to end-stage renal disease. In our single-center study in China, the main clinical manifestations were AKI, CKD, and NS, while the main pathological type was IgAN. Compared with previous strains of SARS-CoV-2, patients with the Omicron infection had a favorable prognosis.
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Injúria Renal Aguda , COVID-19 , Glomerulonefrite por IGA , Insuficiência Renal Crônica , Humanos , SARS-CoV-2 , COVID-19/complicações , COVID-19/patologia , Rim/fisiologia , Rim/patologia , Glomerulonefrite por IGA/complicações , Glomerulonefrite por IGA/patologia , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/patologia , Insuficiência Renal Crônica/complicações , Estudos RetrospectivosRESUMO
Mitochondria-associated endoplasmic reticulum membranes (MAMs) regulate ATG14- and Beclin1-mediated mitophagy and play key roles in the development of diabetic nephropathy (DN). DsbA-L is mainly located in MAMs and plays a role in renoprotection, but whether it activates mitophagy by maintaining MAM integrity remains unclear. In the present study, we found that renal tubular damage was further aggravated in diabetic DsbA-L-/- mice compared with diabetic mice and that this damage was accompanied by disrupted MAM integrity and decreased mitophagy. Furthermore, notably decreased expression of ATG14 and Beclin1 in MAMs extracted from the kidneys of diabetic DsbA-L-/- mice was observed. In vitro, overexpression of DsbA-L reversed the disruption of MAM integrity and enhanced mitophagy in HK-2 cells, a human proximal tubular cell line, after exposure to high-glucose (HG) conditions. Additionally, compared with control mice, DsbA-L-/- mice were exhibited down-regulated expression of helicase with zinc finger 2 (HELZ2) in their kidneys according to transcriptome analysis; HELZ2 serves as a cotranscription factor that synergistically functions with PPARα to promote the expression of mitofusin 2 (MFN-2). Treatment of HK-2 cells with MFN-2 siRNA resulted in MAM uncoupling and decreased mitophagy. Moreover, HG notably reduced the expression of HELZ2 and MFN-2 and inhibited mitophagy, and these effects were partially blocked by overexpression of DsbA-L and altered upon cotreatment with HELZ2 siRNA, HELZ2 overexpression or MK886 (PPARα inhibitor) treatment. These data indicate that DsbA-L alleviates diabetic tubular damage by activating mitophagy through maintenance of MAM integrity via the HELZ2/MFN-2 pathway.
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Diabetes Mellitus Experimental , Nefropatias Diabéticas , Camundongos , Humanos , Animais , Nefropatias Diabéticas/genética , Nefropatias Diabéticas/metabolismo , Diabetes Mellitus Experimental/metabolismo , Mitocôndrias/metabolismo , Proteína Beclina-1/metabolismo , Proteína Beclina-1/farmacologia , Mitofagia/genética , PPAR alfa/metabolismo , RNA Interferente Pequeno/metabolismoRESUMO
BACKGROUND: Alpha-kinase 1 (ALPK1) is a master regulator in inflammation and has been proved to promote renal fibrosis by promoting the production of IL-1ß in diabetic nephropathy (DN) mice. Pyroptosis is involved in high glucose (HG)-induced tubular cells injury, characterized by activation of Gasdermin D (GSDMD) and the release of IL-1ß and IL-18, resulting in inflammatory injury in DN. It is reasonable to assume that ALPK1 is involved in pyroptosis-related tubular injury in DN. However, the mechanism remains poorly defined. METHODS: Immunohistochemistry (IHC) staining was performed to detect the expression of pyroptosis- and fibrosis-related proteins in renal sections of DN patients and DN mice. DN models were induced through injection of streptozotocin combined with a high-fat diet. Protein levels of ALPK1, NF-κB, Caspase-1, GSDMD, IL-1ß, IL-18 and α-SMA were detected by Western blot. HK-2 cells treated with high-glucose (HG) served as an in vitro model. ALPK1 small interfering RNA (siRNA) was transfected into HK-2 cells to down-regulate ALPK1. The pyroptosis rates were determined by flow cytometry. The concentrations of IL-1ß and IL-18 were evaluated by ELISA kits. Immunofluorescence staining was used to observe translocation of NF-κB and GSDMD. RESULTS: The heat map of differentially expressed genes showed that ALPK1, Caspase-1 and GSDMD were upregulated in the DN group. The expression levels of ALPK1, Caspase-1, GSDMD and CD68 were increased in renal biopsy tissues of DN patients by IHC. ALPK1expression and CD68+ macrophages were positively correlated with tubular injury in DN patients. Western blot analysis showed increased expressions of ALPK1, phospho-NF-κB P65, GSDMD-NT, and IL-1ß in renal tissues of DN mice and HK-2 cells, accompanied with increased renal fibrosis-related proteins (FN, α-SMA) and macrophages infiltration in interstitial areas. Inhibition of ALPK1 attenuated HG-induced upregulation expressions of NF-κB, pyroptosis-related proteins Caspase-1, GSDMD-NT, IL-1ß, IL-18, α-SMA, and pyroptosis level in HK-2 cells. Also, the intensity and nuclear translocation of NF-κB and membranous translocation of GSDMD were ameliorated in HG-treated HK-2 cells after treatment with ALPK1 siRNA. CONCLUSIONS: Our data suggest that ALPK1/NF-κB pathway initiated canonical caspase-1-GSDMD pyroptosis pathway, resulting in tubular injury and interstitial inflammation of DN.
Assuntos
Diabetes Mellitus , Nefropatias Diabéticas , Animais , Camundongos , Caspases , Fibrose , Glucose , Inflamação , Interleucina-18 , NF-kappa B/metabolismo , Piroptose , RNA Interferente PequenoRESUMO
PURPOSE: To assess the regional epidemiological trends of kidney diseases over time in the South China using renal biopsy-proven cases. METHODS: This retrospective observational cohort study was conducted at the Institute of Nephrology, Second Xiangya Hospital of Central South University, and encompasses all patients diagnosed with kidney disease via biopsy from 2012 to 2021. RESULTS: The study sample consisted of 10 199 native kidneys, with a male-to-female ratio of 0.91:1 and an average age of 38.74 (±14.53) years. Primary glomerular nephropathy, systemic glomerular nephropathy (SGN), tubulointerstitial disease, and hereditary renal diseases accounted for 66.92 (6825)%, 24.49 (2498)%, 8.06 (822)%, and 0.53 (54)%, respectively. The leading pathologies of primary glomerular nephropathy remained the IgA nephropathy. The frequencies of IgA nephropathy and membranous nephropathy increased significantly, whereas the frequencies of minimal change disease and focal segmental glomerulosclerosis decreased (P < .001) between 2017 and 2021 than in the years 2012 and 2016. An earlier onset of membranous nephropathy was observed in the age group of 45-59 years compared to previous studies. The leading pathologies of SGN were found to be lupus nephritis (758 cases, 30.45%) and hypertension nephropathy (527 cases, 21.17%). The frequencies of hypertension nephropathy and diabetic nephropathy increased between 2017 and 2021 compared to 2012 and 2016 (P < .001), gradually becoming the leading pathological types of SGN. In elderly patients diagnosed with nephrotic syndrome, the frequencies of amyloidosis significantly increased (P < .01). CONCLUSION: Our study may provide insights for kidney disease prevention and public health strategies. What is already known on this topic The pathological spectrum of kidney diseases has undergone significant transformations in the past decade, driven by the escalating incidence of chronic diseases. Although there are studies exploring the renal biopsy findings from various regions in China which present both similarities and differences in epidemiology, few large-scale reports from the South China in recent decades were published. What this study adds Our findings reveal the following key observations: (i) increased proportion of middle-aged patients leading to the increasing average age at the time of biopsyï¼(ii) the frequencies of IgA nephropathy and membranous nephropathy (MN) increased significantly, whereas the frequencies of minimal change disease and focal segmental glomerulosclerosis decreased (P < .001) between 2017 and 2021 than in the years 2012 and 2016; (iii) earlier onset of MN in the age group of 45-59 years old was found in our study; and (iv) a higher frequency of hypertension nephropathy and DN presented over time, and frequency of amyloidosis increased in elderly patients diagnosed with NS. How this study might affect research, practice, or policy This single-center yet a large-scale study of the kidney disease spectrum in South China may provide a reference point for the diagnosis, treatment, and prevention of chronic kidney disease.
Assuntos
Amiloidose , Glomerulonefrite por IGA , Glomerulonefrite Membranosa , Glomerulosclerose Segmentar e Focal , Hipertensão Renal , Nefropatias , Nefrose Lipoide , Pessoa de Meia-Idade , Idoso , Humanos , Masculino , Feminino , Adulto , Lactente , Glomerulonefrite Membranosa/epidemiologia , Glomerulonefrite Membranosa/patologia , Glomerulonefrite por IGA/epidemiologia , Glomerulosclerose Segmentar e Focal/epidemiologia , Nefrose Lipoide/epidemiologia , Estudos Retrospectivos , Nefropatias/epidemiologia , Biópsia , China/epidemiologiaRESUMO
BACKGROUND: Lipid accumulation in tubular cells plays a key role in diabetic kidney disease (DKD). Targeting lipid metabolism disorders has clinical value in delaying the progression of DKD, but the precise mechanism by which molecules mediate lipid-related kidney injury remains unclear. Phosphofurin acidic cluster sorting protein 2 (PACS-2) is a multifunctional sorting protein that plays a role in lipid metabolism. This study determined the role of PACS-2 in lipid-related kidney injury in DKD. METHODS: Diabetes was induced by a high-fat diet combined with intraperitoneal injections of streptozotocin (HFD/STZ) in proximal tubule-specific knockout of Pacs-2 mice (PT-Pacs-2-/- mice) and the control mice (Pacs-2fl/fl mice). Transcriptomic analysis was performed between Pacs-2fl/fl mice and PT-Pacs-2-/- mice. RESULTS: Diabetic PT-Pacs-2-/- mice developed more severe tubule injury and proteinuria compared to diabetic Pacs-2fl/fl mice, which accompanied with increasing lipid synthesis, uptake and decreasing cholesterol efflux as well as lipid accumulation in tubules of the kidney. Furthermore, transcriptome analysis showed that the mRNA level of sterol O-acyltransferase 1 (Soat1) was up-regulated in the kidney of control PT-Pacs-2-/- mice. Transfection of HK2 cells with PACS-2 siRNA under high glucose plus palmitic acid (HGPA) condition aggravated lipid deposition and increased the expression of SOAT1 and sterol regulatory element-binding proteins (SREBPs), while the effect was blocked partially in that of co-transfection of SOAT1 siRNA. CONCLUSIONS: PACS-2 has a protective role against lipid-related kidney injury in DKD through SOAT1/SREBPs signaling.
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Diabetes Mellitus , Nefropatias Diabéticas , Hipercolesterolemia , Animais , Colesterol/metabolismo , Diabetes Mellitus/metabolismo , Nefropatias Diabéticas/etiologia , Glucose/metabolismo , Hipercolesterolemia/metabolismo , Rim/metabolismo , Camundongos , Ácido Palmítico , RNA Mensageiro/metabolismo , RNA Interferente Pequeno , Esteróis/metabolismo , Estreptozocina/metabolismoRESUMO
Cisplatin (Cis) can cause chronic kidney disease (CKD) and promote renal fibrosis, but the underlying mechanism is not fully understood. Hypoxia inducible factor-1α (HIF-1α) can promote renal fibrosis in some kidney diseases, but its role in Cis-induced CKD is still unknown. Notch-1 is a recognized molecule that promotes renal fibrosis under pathological circumstances, and evidence shows that HIF-1α and Notch-1 are closely related to each other. In the present study, mice with HIF-1α gene knockout in proximal tubular cells (PTCs) (PT-HIF-1α-KO) were generated and treated with Cis to induce CKD. A human proximal tubular cell line (HK-2) and primary mouse PTCs were used for in vitro studies. The results showed that HIF-1α was increased in the kidneys of Cis-treated wild-type mice, accompanied by elevated Notch-1, Notch-1 intracellular domain (N1ICD), Hes-1 and renal fibrosis. However, these alterations were partially reversed in PT-HIF-1α-KO mice. Similar results were observed in HK-2 cells and primary mouse PTCs. In addition, treating the cells with Cis induced a marked interaction of HIF-1α and N1ICD. Further inhibiting Notch-1 significantly reduced cellular fibrogenesis but did not affect HIF-1α expression. The data suggested that HIF-1α could promote renal fibrosis in Cis-induced CKD by activating Notch-1 both transcriptionally and post-transcriptionally and that HIF-1α may serve as a potential therapeutic target for Cis-induced CKD.
Assuntos
Fibrose/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Insuficiência Renal Crônica/etiologia , Insuficiência Renal Crônica/metabolismo , Animais , Células Epiteliais/metabolismo , Fibrose/etiologia , Hipóxia/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/deficiência , Rim/metabolismo , Túbulos Renais Proximais/patologiaRESUMO
Renal tubulointerstitial fibrosis (TIF) is a common pathological feature of aristolochic acid (AA) nephropathy (AAN). G2/M arrest of proximal tubular cells (PTCs) is implicated in renal fibrosis of AAN, but the upstream regulatory molecule remains unknown. Hypoxia inducible factor-1α (HIF-1α) promotes renal fibrosis in kidney disease, but the role of HIF-1α in AAN is unclear. Evidence shows that HIF-1α and p21, a known inducer of cellular G2/M arrest, are closely related to each other. To investigate the role of HIF-1α in renal fibrosis of AAN and its effects on p21 expression and PTCs G2/M arrest, mice with HIF-1α gene knockout PTCs (PT-HIF-1α-KO) were generated, and AAN was induced by AA. In vitro tests were conducted on the human PTCs line HK-2 and primary mouse PTCs. HIF-1α and p21 expression, fibrogenesis, and G2/M arrest of PTCs were determined. Results showed that HIF-1α was upregulated in the kidneys of wild-type (WT) AAN mice, accompanied by p21 upregulation, PTCs G2/M arrest and renal fibrosis, and these alterations were reversed in PT-HIF-1α-KO AAN mice. Similar results were observed in HK-2 cells and were further confirmed in primary PTCs from PT-HIF-1α-KO and WT mice. Inhibiting p21 in HK-2 cells and primary PTCs did not change the expression of HIF-1α, but G2/M arrest and fibrogenesis were reduced. These data indicate that HIF-1α plays a key role in renal fibrosis in AAN by inducing PTCs G2/M arrest modulated through p21. HIF-1α may serve as a potential therapeutic target for AAN.
Assuntos
Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Células Epiteliais/citologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/fisiologia , Túbulos Renais Proximais , Nefrite Intersticial/metabolismo , Animais , Ácidos Aristolóquicos , Linhagem Celular , Fibrose/induzido quimicamente , Pontos de Checagem da Fase G2 do Ciclo Celular , Humanos , Túbulos Renais Proximais/citologia , Túbulos Renais Proximais/patologia , Camundongos , Camundongos KnockoutRESUMO
Ectopic fat deposition (EFD) in the kidney has been shown to play a causal role in diabetic nephropathy; however, the mechanism underlying EFD remains elusive. By transcriptome analysis, we found decreased expression levels of disulfide-bond A oxidoreductase-like protein (DsbA-L) in the kidneys of diabetic mice (induced by high-fat diet plus Streptozotocin) compared with control mice. Increased expression of adipocyte differentiation-related protein and abnormal levels of collagen I, fibronectin, and phosphorylated 5'AMP-activated kinase (p-AMPK), adipose triglyceride lipase (p-ATGL), and HMG-CoA reductase (p-HMGCR) were also observed in diabetic mice. These alterations were accompanied by deposition of lipid droplets in the kidney, and were more pronounced in diabetic DsbA-L knockout mice. In vitro, overexpression of DsbA-L ameliorated high glucose-induced intracellular lipid droplet deposition in a human proximal tubular cell line, and DsbA-L siRNA aggravated lipid droplet deposition and reduced the levels of p-AMPK, p-ATGL, and p-HMGCR. High glucose and palmitic acid treatment enhanced the expression of interleukin-1ß and interleukin-18; these enhancements were further increased after treatment with DsbA-L siRNA but alleviated by co-treatment with an AMPK activator. In kidney biopsy tissue from patients with diabetic nephropathy, DsbA-L expression was negatively correlated with EFD and tubular damage. Collectively, these results suggest that DsbA-L has a protective role against EFD and lipid-related kidney damage in diabetic nephropathy. Activation of the AMPK pathway is a potential mechanism underlying DsbA-L action in the kidney.
Assuntos
Nefropatias Diabéticas/patologia , Glutationa Transferase/metabolismo , Rim/patologia , Metabolismo dos Lipídeos , Adenilato Quinase/metabolismo , Adulto , Animais , Biópsia , Linhagem Celular , Colesterol/biossíntese , Diabetes Mellitus Experimental/etiologia , Diabetes Mellitus Experimental/metabolismo , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/metabolismo , Dieta Hiperlipídica/efeitos adversos , Feminino , Glutationa Transferase/genética , Humanos , Hidroximetilglutaril-CoA Redutases/metabolismo , Rim/citologia , Gotículas Lipídicas/patologia , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , RNA Interferente Pequeno/metabolismo , Estreptozocina/toxicidadeRESUMO
Endoplasmic reticulum (ER) degradation via autophagy is a process that maintains ER homeostasis when cells are in a state of stress and is associated with many diseases; however, the role of hypoxia inducible factor-1α (HIF-1α)-mediated ER degradation and the related regulatory pathway in acute kidney injury (AKI) still needs to be further established. In the present study, an in vivo AKI model was induced in mice via the ischemiaâreperfusion (IR) method. The results revealed that HIF-1α and BNIP3 were increased, and autophagy and ER degradation were activated in the kidneys of AKI mice, whereas HIF-1α knockout significantly inhibited BNIP3, autophagy and ER degradation, accompanied by aggravated kidney injury. Overexpression of HIF-1α in vitro significantly increased BNIP3, autophagy and ER degradation, whereas inhibition of BNIP3 significantly reversed the effects of HIF-1α. In addition, the in vitro inhibition of autophagy with chloroquine significantly reversed the effects of HIF-1α on cell apoptosis. Moreover, selectively overexpressing BNIP3 on the ER membrane significantly increased ER degradation via autophagy and decreased cell apoptosis in vitro. These data indicate that HIF-1α/BNIP3-mediated ER degradation via autophagy in tubular cells protects against IR-induced AKI.
RESUMO
BACKGROUND: Lipid metabolism imbalance is involved in the mechanism of renal tubular injury in diabetic kidney disease (DKD). Fatty acid binding protein 4 (FABP4) has been reported to participate in cellular lipid toxicity. However, the expression of FABP4 in renal tissues of DKD and its correlation with clinical/ pathological parameters and prognosis have not been studied. METHODS: A retrospective cohort study was conducted in 108 hospitalized Type 2 diabetes (T2D) patients with renal injury, including 70 with DKD and 38 with NDKD (non-DKD). Clinical features, pathological findings, and follow-up parameters were collected. Serum and urine FABP4 were detected by ELISA. An immunohistochemistry stain was used to determine FABP4 in renal tubulointerstitium. A double immunofluorescence stain was employed to assess FABP4- and CD68-positive macrophages. Correlation analysis, logistic regression models, receiver operating characteristic (ROC), and Kaplan-Meier survival curve were performed for statistical analysis. RESULTS: DKD patients had increased expression of FABP4 and ectopic fat deposition in tubules. As shown by correlation analyses, FABP4 expression in renal tubules was positively correlated with UNAG (r=0.589, p=0.044) and ESRD (r=0.740, p=0.004). Multivariate regression analysis revealed that UNAG level was correlated with FABP4 expression level above median value (odds ratio:1.154, 95% confidence interval:1.009-1.321, p=0.037). High-expression of FABP4 in renal tubules of DKD was at an increased risk of ESRD. Increased FABP4 expression in inflammatory cells was also associated with ESRD in DKD. CONCLUSION: High-expression of FABP4 is involved in the pathogenesis of renal tubular lipid injury and is a risk factor for poor prognosis in DKD patients.
Assuntos
Nefropatias Diabéticas , Proteínas de Ligação a Ácido Graxo , Túbulos Renais , Humanos , Proteínas de Ligação a Ácido Graxo/metabolismo , Masculino , Feminino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Túbulos Renais/metabolismo , Túbulos Renais/patologia , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Nefropatias Diabéticas/diagnóstico , Fatores de Risco , Idoso , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/complicaçõesRESUMO
OBJECTIVE: The objective of this study is to evaluate the regulatory mechanism between P66Shc and ferroptosis in cisplatin-induced acute kidney injury (CP-AKI). METHODS: A CP-AKI model was constructed both in vivo and in vitro using C57BL/6 mice and HK-2 cells, respectively. Renal histopathological injury, reactive oxygen species (ROS), and apoptosis were detected. Some parameters of ferroptosis (e.g. 4HNE and GPX4) and the expression of P66Shc/ P-P66Shc both in mitochondria and cytoplasm were tested. In in vitro studies, HK-2 cells were incubated with CP (50 uM); additionally, Fer1 and P66Shc siRNA were applied to explore the molecular regulatory mechanism of P66Shc in ferroptosis. The levels of mitochondrial ROS, apoptosis and the expression of 4HNE,GPX4, P66Shc, and P-P66Shc were tested. Furthermore, the mitochondrial translocation of P66Shc was detected. RESULTS: CP treatment caused elevation of Scr, BUN and renal MDA levels and decreased renal SOD, GSH-PX and GPX4 levels. CP enhanced the expression of 4HNE, P66Shc and P-P66Shc both in vivo and in vitro. Renal oxidative stress and apoptosis were significantly increased in CP-AKI mice. Electron microscopy examination indicated obvious mitochondria injury in renal tubular cells of CP-AKI mice. The level of ferroptosis and the translocation of P-P66Shc from the cytoplasm to mitochondria were significantly increased in HK-2 cells under CP condition, and these effects were obviously blocked by P66Shc siRNA treatment. Conversely, pretreatment with the ferroptosis inhibitor (Fer1) had no effect on the expression and mitochondria translocation of PP66Shc under CP condition. CONCLUSION: Mitochondrial translocation of P66Shc could result in mitochondrial injury and lipid peroxide accumulation, which ultimately led to ferroptosis and aggravated CPinduced AKI.
Assuntos
Injúria Renal Aguda , Cisplatino , Ferroptose , Proteínas Adaptadoras da Sinalização Shc , Animais , Camundongos , Injúria Renal Aguda/induzido quimicamente , Linhagem Celular , Cisplatino/toxicidade , Camundongos Endogâmicos C57BL , Espécies Reativas de Oxigênio/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Proteínas Adaptadoras da Sinalização Shc/genética , Proteínas Adaptadoras da Sinalização Shc/metabolismo , Proteína 1 de Transformação que Contém Domínio 2 de Homologia de Src/genética , Proteína 1 de Transformação que Contém Domínio 2 de Homologia de Src/metabolismoRESUMO
Henan Province is located in central China and rich in domestic pig populations; Huainan (HN) pigs are one of three Henan indigenous breeds with great performance, including early maturation, strong disease resistance and high meat quality. Yunan (YN) black pigs are a typical, newly cultivated breed, synthesized between HN pigs and American Duroc, and are subjected to selection for important traits, such as fast growth and excellent meat quality. However, the genomic differences, selection signatures and loci associated with important economic traits in YN black pigs and HN pigs are still not well understood. In this study, based on high-density SNP chip analysis of 159 samples covering commercial DLY (Duroc × Landrace × Large White) pigs, HN pigs and YN black pigs, we performed a comprehensive analysis of phylogenetic relationships and genetic diversity among the three breeds. Furthermore, we used composite likelihood ratio tests (CLR) and F-statistics (Fst) to identify specific signatures of selection associated with important economic traits and potential candidate genes. We found 147 selected regions (top 1%) harboring 90 genes based on genetic differentiation (Fst) in the YN-DLY group. In the HN-DLY group, 169 selected regions harbored 58 genes. In the YN-HN group, 179 selected regions harbored 77 genes. In addition, the QTLs database with the most overlapping regions was associated with triglyceride level, number of mummified pigs, hemoglobin and loin muscle depth for YN black pigs, litter size and intramuscular fat content for HN pigs, and humerus length, linolenic acid content and feed conversion ratio mainly in DLY pigs. Of note, overlapping 14 tissue-specific promoters' annotation with the top Fst 1% selective regions systematically demonstrated the muscle-specific and hypothalamus-specific regulatory elements in YN black pigs. Taken together, these results contribute to an accurate knowledge of crossbreeding, thus benefitting the evaluation of production performance and improving the genome-assisted breeding of other important indigenous pig in the future.
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Locos de Características Quantitativas , Sus scrofa , Suínos/genética , Animais , Filogenia , Sus scrofa/genética , Fenótipo , GenômicaRESUMO
The endoplasmic reticulum (ER) is the most vigorous organelle in intracellular metabolism and is involved in physiological processes such as protein and lipid synthesis and calcium ion transport. Recently, the abnormal function of the ER has also been reported to be involved in the progression of kidney disease, especially in diabetic nephropathy (DN). Here, we reviewed the function of the ER and summarized the regulation of homeostasis through the UPR and ER-phagy. Then, we also reviewed the role of abnormal ER homeostasis in residential renal cells in DN. Finally, some ER stress activators and inhibitors were also summarized, and the possibility of maintaining ER homeostasis as a potential therapeutic target for DN was discussed.
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Diabetes Mellitus , Nefropatias Diabéticas , Humanos , Nefropatias Diabéticas/tratamento farmacológico , Retículo Endoplasmático , Homeostase , Estresse do Retículo Endoplasmático , Células EpiteliaisRESUMO
Cisplatin is one of the major causes of acute kidney injury (AKI) in clinical practice, and ferroptosis is an essential form of cell death in cisplatin-induced AKI (CP-AKI). WW domain binding protein-2 (WBP2), a molecular chaperon, is involved in the progression of various malignancies, but its role in renal injuries has not been investigated. Our present study employed bioinformatics analysis to identify WBP2 as a potential modulator of AKI and ferroptosis. Preliminary laboratory investigations showed that WBP2, highly expressed in renal proximal tubular cells, was downregulated in CP-AKI. Further studies demonstrated that WBP2 decelerated ferroptosis to alleviate CP-AKI. Mechanistically, WBP2 interacted with glutathione peroxidase 4 (GPX4, a key detoxicating enzyme for ferroptosis) via its PPXY1 motif to inhibit ferroptosis. Furthermore, the in-depth investigations revealed that WBP2 competed with heat shock cognate protein 70 (HSC70) for the binding with the KEFRQ-like motifs of GPX4, leading to the deceleration of chaperon-mediated autophagy of GPX4. All in all, this study indicated the beneficial effect of WBP2 in CP-AKI and its relevance with ferroptosis, thus providing a novel insight into the modulation of ferroptosis in cisplatin-related nephropathy.
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Injúria Renal Aguda , Ferroptose , Humanos , Cisplatino/efeitos adversos , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/genética , Rim , Morte Celular , Proteínas de Choque Térmico HSP70 , TransativadoresRESUMO
Metabolic syndrome is a complex metabolic disorder that often clinically manifests as obesity, insulin resistance/diabetes, hyperlipidemia, and hypertension. With the development of social and economic systems, the incidence of metabolic syndrome is increasing, bringing a heavy medical burden. However, there is still a lack of effective prevention and treatment strategies. Fibroblast growth factor 21 (FGF21) is a member of the human FGF superfamily and is a key protein involved in the maintenance of metabolic homeostasis, including reducing fat mass and lowering hyperglycemia, insulin resistance and dyslipidemia. Here, we review the current regulatory mechanisms of FGF21, summarize its role in obesity, diabetes, hyperlipidemia, and hypertension, and discuss the possibility of FGF21 as a potential target for the treatment of metabolic syndrome.
Assuntos
Diabetes Mellitus , Hiperlipidemias , Hipertensão , Resistência à Insulina , Síndrome Metabólica , Humanos , Síndrome Metabólica/complicações , Fatores de Crescimento de Fibroblastos/metabolismo , Obesidade/metabolismoRESUMO
Metabolic syndrome is a complex metabolic disorder, its main clinical manifestations are obesity, hyperglycemia, hypertension and hyperlipidemia. Although metabolic syndrome has been the focus of research in recent decades, it has been proposed that the occurrence and development of metabolic syndrome is related to pathophysiological processes such as insulin resistance, adipose tissue dysfunction and chronic inflammation, but there is still a lack of favorable clinical prevention and treatment measures for metabolic syndrome. Multiple studies have shown that myostatin (MSTN), a member of the TGF-ß family, is involved in the development and development of obesity, hyperlipidemia, diabetes, and hypertension (clinical manifestations of metabolic syndrome), and thus may be a potential therapeutic target for metabolic syndrome. In this review, we describe the transcriptional regulation and receptor binding pathway of MSTN, then introduce the role of MSTN in regulating mitochondrial function and autophagy, review the research progress of MSTN in metabolic syndrome. Finally summarize some MSTN inhibitors under clinical trial and proposed the use of MSTN inhibitor as a potential target for the treatment of metabolic syndrome.
Assuntos
Resistência à Insulina , Síndrome Metabólica , Humanos , Síndrome Metabólica/tratamento farmacológico , Síndrome Metabólica/metabolismo , Miostatina/metabolismo , Músculo Esquelético/metabolismo , Resistência à Insulina/fisiologia , Obesidade/complicações , Obesidade/metabolismoRESUMO
To investigate the effects and mechanism of Vitamin D receptor (VDR) signaling on arteriovenous fistula (AVF) endothelial cell injury. Venous tissues of AVF stenosis patients were collected and analyzed, vascular morphology, reactive oxygen species (ROS), and the expression of VDR, P66Shc, fibronectin (FN), collagen-1 (Col-1) were detected. In addition, human umbilical vein endothelial cells (HUVECs) was used in in vitro studies. HUVECs was incubated with transforming growth factor-beta (TGF-ß, 50 ng/ml). Aditionally, paricalcitol, VDR overexpression plasmid and Pin1 inhibitor Juglone were used to investigate the regulatory mechanism of VDR in mitochondrial ROS. The parameters of ROS (e.g. MitoSox) and the expression of FN, Col-1 were tested. Moreover, the mitochondrial translocation of P66Shc was analyzed. The expression of VDR was obviously decreased in the venous tissues of AVF stenosis patients. On the contrary, the expression of P66Shc, P-P66Shc, FN, Col-1 and 8-OHdG were increased significantly in the venous tissues of AVF stenosis patients (P < 0.05). In line with this, the level of mitochondrial ROS and the expression of P66Shc, P-P66Shc, FN, Col-1 increased obviously in HUVECs cells under TGF-ß condition. Both VDR over-expression plasmid and Pin1 inhibitor Juglone could alleviate TGF-ß induced endothelial injury. Mechanistically, VDR overexpression plasmid and Juglone could inhibit the expression of Pin1, and then restrain P66Shc mitochondrial translocation, eventually reduce the level of mitochondrial ROS. Our research indicated that activation of VDR could alleviate venous endothelial cell dysfunction through inhibiting Pin1-mediated mitochondrial translocation of P66Shc and consequently reducing mitochondrial ROS. It suggested that VDR signaling might be an effective target for AVF stenosis treatment.
Assuntos
Fístula Arteriovenosa , Humanos , Espécies Reativas de Oxigênio/metabolismo , Proteína 1 de Transformação que Contém Domínio 2 de Homologia de Src/genética , Proteína 1 de Transformação que Contém Domínio 2 de Homologia de Src/metabolismo , Constrição Patológica/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Fístula Arteriovenosa/metabolismo , Receptores de Calcitriol/genética , Receptores de Calcitriol/metabolismoRESUMO
Mitochondria, which are the energy factories of the cell, participate in many life activities, and the kidney is a high metabolic organ that contains abundant mitochondria. Renal aging is a degenerative process associated with the accumulation of harmful processes. Increasing attention has been given to the role of abnormal mitochondrial homeostasis in renal aging. However, the role of mitochondrial homeostasis in renal aging has not been reviewed in detail. Here, we summarize the current biochemical markers associated with aging and review the changes in renal structure and function during aging. Moreover, we also review in detail the role of mitochondrial homeostasis abnormalities, including mitochondrial function, mitophagy and mitochondria-mediated oxidative stress and inflammation, in renal aging. Finally, we describe some of the current antiaging compounds that target mitochondria and note that maintaining mitochondrial homeostasis is a potential strategy against renal aging.
RESUMO
Autophagy of endoplasmic reticulum (ER-phagy) selectively removes damaged ER through autophagy-lysosome pathway, acting as an adaptive mechanism to alleviate ER stress and restore ER homeostasis. However, the role and precise mechanism of ER-phagy in tubular injury of diabetic kidney disease (DKD) remain obscure. In the present study, we demonstrated that ER-phagy of renal tubular cells was severely impaired in streptozocin (STZ)-induced diabetic mice, with a decreased expression of phosphofurin acidic cluster sorting protein 2 (PACS-2), a membrane trafficking protein which was involved in autophagy, and a reduction of family with sequence similarity 134 member B (FAM134B), one ER-phagy receptor. These changes were further aggravated in mice with proximal tubule specific knockout of Pacs-2 gene. In vitro, transfection of HK-2 cells with PACS-2 overexpression plasmid partially improved the impairment of ER-phagy and the reduction of FAM134B, both of which were induced in high glucose ambience; while the effect was blocked by FAM134B siRNA. Mechanistically, PACS-2 interacted with and promoted the nuclear translocation of transcription factor EB (TFEB), which was reported to activate the expression of FAM134B. Collectively, these data unveiled that PACS-2 deficiency aggravates renal tubular injury in DKD via inhibiting ER-phagy through TFEB/FAM134B pathway.