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Chronic Kidney Disease (CKD) has emerged as a global public health concern, with its primary pathological basis being Renal Fibrosis (RF), crucial to halt its progression to End-Stage Renal Disease (ESRD). However, effective treatment options are currently lacking. Therefore, exploring the mechanisms of RF, identifying drug targets and diagnostic biomarkers are important. In this study, we identified ADAMTS16 as a newly expressed regulatory factor highly expressed in renal fibrosis tissue. ADAMTS16 interacts with latency-associated peptide (LAP)-transforming growth factor (TGF)-ß, leading to the activation of TGF-ß. Loss of ADAMTS16 expression effectively reduces TGF-ß-dependent transcription activity. Furthermore, the use of RRFR tetrapeptide derived from ADAMTS16 can activate the TGF-ß/Smad signaling axis, promoting RF. In summary, ADAMTS16 is induced in the progression of CKD, interacting with LAP-TGF-ß and potentially activating SMAD2/3. Therefore, targeting ADAMTS16 may serve as a crucial new strategy to alleviate RF and treat CKD patients.
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AlGaInP-based red light emitting diodes (LEDs) are considered as promising light sources in future full-color displays. At present, vertical chip configuration is still the mainstream device structure of AlGaInP-based red LEDs. However, current crowding around p-electrode severely hinders an efficient improvement. Here, we propose a Schottky-contact current blocking layer (SCBL) to enhance current spreading and to improve light extraction efficiency of AlGaInP-based red vertical miniaturized LEDs (mini-LEDs). By utilizing the Schottky contact between ITO and p-GaP, the SCBL can hinder current crowding around the p-electrode. The current is forced to inject into an active region through a p-GaP+ ohmic contact layer, avoiding light absorption by p-electrode. Through the transfer length method, the Schottky contact characteristics between the ITO and p-GaP as well as the ohmic contact characteristics between ITO and p-GaP+ are demonstrated. Benefiting from superior current spreading and improved light extraction, a mini-LED with SCBL realizes an enhancement of 31.8% in external quantum efficiency (EQE) at 20â mA in comparison with a mini-LED without SCBL.
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BACKGROUND: Patients with diabetes are prone to acute kidney injury (AKI) with a high mortality rate, poor prognosis, and a higher risk of progression to chronic kidney disease than non-diabetic patients. METHODS: Streptozotocin (STZ)-treated type 1 and db/db type 2 diabetes model were established, AKI model was induced in mice by ischemia-reperfusion injury(IRI). Mouse proximal tubular cell cells were subjected to high glucose and hypoxia-reoxygenation in vitro. Transcriptional RNA sequencing was performed for clustering analysis and target gene screening. Renal structural damage was determined by histological staining, whereas creatinine and urea nitrogen levels were used to measure renal function. RESULTS: Deteriorated renal function and renal tissue damage were observed in AKI mice with diabetic background. RNA sequencing showed a decrease in fatty acid oxidation (FAO) pathway and an increase in abnormal glycolysis. Treatment with Dapa, Sitagliptin(a DPP-4 inhibitor)and insulin reduced blood glucose levels in mice, and improved renal function. However, Dapa had a superior therapeutic effect and alleviated aberrant FAO and glycosis. Dapa reduced cellular death in cultured cells under high glucose hypoxia-reoxygenation conditions, alleviated FAO dysfunction, and reduced abnormal glycolysis. RNA sequencing showed that SIRT3 expression was reduced in diabetic IRI, which was largely restored by Dapa intervention. 3-TYP, a SIRT3 inhibitor, reversed the renal protective effects of Dapa and mediated abnormal FAO and glycolysis in mice and tubular cells. CONCLUSION: Our study provides experimental evidence for the use of Dapa as a means to reduce diabetic AKI by ameliorating metabolic reprogramming in renal tubular cells.
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BACKGROUND: Although it is acknowledged that ischemia-reperfusion injury is the primary pathology of cold storage-associated kidney transplantation, its underlying mechanism is not well elucidated. METHODS: To extend the understanding of molecular events and mine hub genes posttransplantation, we performed bulk RNA sequencing at different time points (24 h, day 7, and day 14) on a murine kidney transplantation model with prolonged cold storage (10 h). RESULTS: In the present study, we showed that genes related to the regulation of apoptotic process, DNA damage response, cell cycle/proliferation, and inflammatory response were steadily elevated at 24 h and day 7. The upregulated gene profiling delicately transformed to extracellular matrix organization and fibrosis at day 14. It is prominent that metabolism-associated genes persistently took the first place among downregulated genes. The gene ontology terms of particular note to enrich are fatty acid oxidation and mitochondria energy metabolism. Correspondingly, the key enzymes of the above processes were the products of hub genes as recognized. Moreover, we highlighted the proximal tubular cell-specific increased genes at 24 h by combining the data with public RNA-Seq performed on proximal tubules. We also focused on ferroptosis-related genes and fatty acid oxidation genes to show profound gene dysregulation in kidney transplantation. CONCLUSIONS: The comprehensive characterization of transcriptomic analysis may help provide diagnostic biomarkers and therapeutic targets in kidney transplantation.
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BACKGROUND: Acute kidney injury (AKI) is a common clinical disorder with complex etiology and poor prognosis, and currently lacks specific and effective treatment options. Mitochondrial dynamics dysfunction is a prominent feature in AKI, and modulation of mitochondrial morphology may serve as a potential therapeutic approach for AKI. METHODS: We induced ischemia-reperfusion injury (IRI) in mice (bilateral) and Bama pigs (unilateral) by occluding the renal arteries. ATP depletion and recovery (ATP-DR) was performed on proximal renal tubular cells to simulate in vitro IRI. Renal function was evaluated using creatinine and urea nitrogen levels, while renal structural damage was assessed through histopathological staining. The role of Drp1 was investigated using immunoblotting, immunohistochemistry, immunofluorescence, and immunoprecipitation techniques. Mitochondrial morphology was evaluated using confocal microscopy. RESULTS: Renal IRI induced significant mitochondrial fragmentation, accompanied by Dynamin-related protein 1 (Drp1) translocation to the mitochondria and Drp1 phosphorylation at Ser616 in the early stages (30 min after reperfusion), when there was no apparent structural damage to the kidney. The use of the Drp1 inhibitor P110 significantly improved kidney function and structural damage. P110 reduced Drp1 mitochondrial translocation, disrupted the interaction between Drp1 and Fis1, without affecting the binding of Drp1 to other mitochondrial receptors such as MFF and Mid51. High-dose administration had no apparent toxic side effects. Furthermore, ATP-DR induced mitochondrial fission in renal tubular cells, accompanied by a decrease in mitochondrial membrane potential and an increase in the translocation of the pro-apoptotic protein Bax. This process facilitated the release of dsDNA, triggering the activation of the cGAS-STING pathway and promoting inflammation. P110 attenuated mitochondrial fission, suppressed Bax mitochondrial translocation, prevented dsDNA release, and reduced the activation of the cGAS-STING pathway. Furthermore, these protective effects of P110 were also observed renal IRI model in the Bama pig and folic acid-induced nephropathy in mice. CONCLUSIONS: Dysfunction of mitochondrial dynamics mediated by Drp1 contributes to renal IRI. The specific inhibitor of Drp1, P110, demonstrated protective effects in both in vivo and in vitro models of AKI.
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Injúria Renal Aguda , Animais , Camundongos , Suínos , Proteína X Associada a bcl-2 , Dinaminas , Nucleotidiltransferases , Trifosfato de AdenosinaRESUMO
AlGaInP-based light-emitting diodes (LEDs) suffer from a low external quantum efficiency (EQE), which is mainly restrained by the poor light extraction efficiency. Here, we demonstrate AlGaInP-based vertical miniaturized-LEDs (mini-LEDs) with a porous n-AlGaInP surface using a wet etching process to boost light extraction. We investigated the effects of etching time on the surface morphology of the porous n-AlGaInP surface. We found that as the etching time is prolonged, the density of pores increases initially and decreases subsequently. In comparison with the vertical mini-LED with a smooth n-AlGaInP surface, the vertical mini-LEDs with the porous n-AlGaInP surface reveal improvement in light output power and EQE, meanwhile, without the deterioration of electrical performance. The highest improvement of 38.9% in EQE measured at 20â mA is observed from the vertical mini-LED with the maximum density of the pores. Utilizing a three-dimensional finite-difference time-domain method, we reveal the underlying mechanisms of improved performance, which are associated with suppressed total internal reflection and efficient light scattering effect of the pores.
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BACKGROUND: This study aimed to analyze trends in the burden of myocarditis in the Chinese population during 1990-2019. METHODS: The Global Burden of Disease (GBD) database aims to assess the burden of various diseases and injuries on a global scale, and the contribution of relevant risk factors to the burden of disease was also included. In this study, we collected age-standardized incidence and mortality rates for myocarditis in China from 1990 to 2019 using GBD 2019. The age-period-cohort model was utilized to calculate local drift, longitudinal age patterns, as well as the ratios of period and cohort. RESULTS: The age-standardized incidence and mortality rates of myocarditis in both men and women presented a decreasing trend during 1990-2019 [average annual percentage change (AAPC) of men = -0.202 (95% CI: -0.213 to -0.191); AAPC of women = -0.263 (95% CI: -0.27 to -0.256) for incidence; AAPC of men = -0.233 (95% CI: -0.371 to -0.094); AAPC of women = -0.872 (95% CI: -1.112 to -0.631) for mortality]. Longitudinal age curves showed that myocarditis incidence and mortality rates elevated with age among individuals aged 15-95+ years, with a higher growth rate in men than in women. The period and cohort ratios for both men and women showed similar decreasing trends. Local drift values for the incidence and mortality rates of myocarditis showed an increasing trend among individuals aged 70-75 years and above. CONCLUSION: Although the overall burden of myocarditis in China presented a decreasing trend during 1990-2019, the male and elderly populations still have a higher risk of incidence and mortality. Therefore, it is essential for the health-care system to introduce effective prevention and treatment measures for myocarditis.
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Cisplatin, an effective anti-cancer drug, always causes acute kidney injury (AKI) by inducing mitochondrial damage. PIM1 is a serine/threonine kinase, which has been shown to regulate mitochondrial function. However, the role and mechanisms of PIM1 in cisplatin-induced AKI remain unexplored. This study aimed to investigate the effects of PIM1 in cisplatin-induced AKI and its underlying mechanisms. To established Cisplatin-induced AKI model, mice were given a single intraperitoneal injection(20 mg/kg) and BUMPT cells were treated with cisplatin(20 µM). PIM1 inhibitor AZD1208 was used to inhibit PIM1 and PIM1-experssing adenovirus was used to overexpress PIM1. Drp1 inhibitor P110 and pcDNA3-Drp1K38A were used to inhibit the activation of Drp1 and mitochondrial fission. The indicators of renal function, renal morphology, apoptosis and mitochondrial dysfunction were assessed to evaluate cisplatin-induced nephrotoxicity. We observed that PIM1 was activated in cisplatin-induced AKI in vivo and cisplatin-induced tubular cells injury in vitro. PIM1 inhibition aggravated cisplatin-induced AKI in vivo, while PIM1 overexpression attenuated cisplatin-induced kidney injury in vivo and in vitro. Moreover, inhibiting PIM1 exacerbated mitochondrial damage in mice, but overexpressing PIM1 relieved mitochondrial damage in mice and BUMPT cells. In mice and BUMPT cells, inhibiting PIM1 deregulated the expression of p-Drp1S637, overexpressing PIM1 upregulated the ex-pression of p-Drp1S637. And inhibiting Drp1 activity alleviated cell damage in BUMPT cells with PIM1 knockdown or inhibition. This study demonstrated the protective effect of PIM1 in cisplatin-induced AKI, and regulation of Drp1 activation might be the underlying mechanism. Altogether, PIM1 may be a potential therapeutic target for cisplatin-induced AKI.
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Injúria Renal Aguda , Antineoplásicos , Animais , Camundongos , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/tratamento farmacológico , Antineoplásicos/farmacologia , Apoptose , Células Cultivadas , Cisplatino/farmacologia , Rim/metabolismo , Camundongos Endogâmicos C57BLRESUMO
The mechanism underlying acute kidney injury (AKI) and AKI-to-Chronic kidney disease (CKD) transition remains unclear, but mitochondrial dysfunction may be a key driving factor. Literature reports suggest that dual-specificity phosphatase 1 (DUSP1) plays a critical role in maintaining mitochondrial function and structural integrity. In this study, ischemic Acute Kidney Injury (AKI) and post-ischemic fibrosis models were established by clamping the renal pedicle with different reperfusion times. To investigate the role of DUSP1, constitutional Dusp1 knockout mice and tubular-specific Sting knockout mice were used. Mitochondrial damage was assessed through electron microscopy observation, measurements of mitochondrial membrane potential, mtDNA release, and BAX translocation. We found that Dusp1 expression was significantly upregulated in human transplant kidney tissue and mouse AKI tissue. Dusp1 gene deletion exacerbated acute ischemic injury, post-ischemic renal fibrosis, and tubular mitochondrial dysfunction in mice. Mechanistically, DUSP1 could directly bind to JNK, and DUSP1 deficiency could lead to aberrant phosphorylation of JNK and BAX mitochondria translocation. BAX translocation promoted mitochondrial DNA (mtDNA) leakage and activated the cGAS-STING pathway. Inhibition of JNK or BAX could inhibit mtDNA leakage. Furthermore, STING knockout or JNK inhibition could significantly mitigate the adverse effects of DUSP1 deficiency in ischemic AKI model. Collectively, our findings suggest that DUSP1 is a regulator for the protective response during AKI. DUSP1 protects against AKI by preventing BAX-induced mtDNA leakage and blocking excessive activation of the cGAS-STING signaling axis through JNK dephosphorylation.
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Injúria Renal Aguda , Traumatismo por Reperfusão , Animais , Humanos , Camundongos , Injúria Renal Aguda/metabolismo , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo , DNA Mitocondrial/genética , DNA Mitocondrial/metabolismo , Fosfatase 1 de Especificidade Dupla/genética , Fosfatase 1 de Especificidade Dupla/metabolismo , Rim/metabolismo , Camundongos Knockout , Mitocôndrias/metabolismo , Nucleotidiltransferases/metabolismo , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/metabolismoRESUMO
OBJECTIVES: This study aimed to describe the temporal trends in age and gender burdens of rheumatic heart disease (RHD) in China from 1990 to 2019, including incidence, prevalence, mortality, and disability-adjusted life years (DALYs), and to compare them with the global burden of the disease. METHODS: Using open data from the Global Burden of Disease (GBD) database from 1990 to 2019, this study analyzed the characteristics of RHD burden in China and worldwide, including changes in incidence, prevalence, mortality, and DALYs. Joinpoint was used to calculate the average annual percentage change (AAPC) and the corresponding 95% confidence interval (95% CI) to reflect the trends in the burden of RHD. A comprehensive comparative analysis of the differences in RHD burden between China and the rest of the world was conducted from multiple dimensions, including age, gender, and time periods. RESULTS: From 1990 to 2019, the age-standardized incidence rate (ASIR) of RHD in China decreased from 29.62/100,000 to 23.95/100,000, while the global ASIR increased from 32.69/100,000 to 37.40/100,000. The age-standardized prevalence rate (ASPR) in China decreased from 446.15/100,000 to 390.24/100,000, while the global ASPR increased from 451.56/100,000 to 513.68/100,000. The age-standardized rates of mortality (ASMR) in China decreased from 18.11/100,000 to 4.04/100,000, while the global ASMR decreased from 8.94/100,000 to 3.85/100,000. The age-standardized DALY rate (ASDR) in China decreased from 431.45/100,000 to 93.73/100,000, while the global ASDR decreased from 283.30/100,000 to 132.88/100,000. The AAPC of ASIR, ASPR, ASMR, and ASDR in China was - 0.73%, -0.47%, -5.10%, and - 5.21%, respectively, while the AAPC of the global burden of RHD was 0.48%, 0.45%, -2.87%, and - 2.58%, respectively. The effects of age and gender on the burden of RHD were different. ASIR generally decreased with increasing age, while ASPR increased first and then decreased. ASMR and ASDR increased with increasing age. Women had higher incidence and mortality rates of RHD than men. CONCLUSION: From 1990 to 2019, the incidence, prevalence, mortality, and DALYs of RHD in China decreased, indicating a relative reduction in the burden of RHD in China. The burden of RHD is age-related, with a higher prevalence observed in the younger population, a peak incidence among young adults, and a higher mortality rate among the elderly population. Women are more susceptible to RHD and have a higher risk of mortality than men. Given China's large population and aging population, RHD remains a significant public health challenge in China.
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Cardiopatia Reumática , Masculino , Adulto Jovem , Humanos , Idoso , Feminino , Cardiopatia Reumática/diagnóstico , Cardiopatia Reumática/epidemiologia , China/epidemiologia , Envelhecimento , Bases de Dados Factuais , Saúde Pública , Anos de Vida Ajustados por Qualidade de Vida , Saúde Global , IncidênciaRESUMO
In the followup of hospitalized patients with acute kidney injury (AKI), it has been observed that 1530% of these patients progress to develop chronic kidney disease (CKD). Impaired adaptive repair of the kidneys following AKI is a fundamental pathophysiological mechanism underlying renal fibrosis and the progression to CKD. Deficient repair of proximal tubular epithelial cells is a key factor in the progression from AKI to CKD. However, the molecular mechanisms involved in the regulation of fibrotic factor paracrine secretion by injured tubular cells remain incompletely understood. Transcriptome analysis and an ischemiareperfusion injury (IRI) model were used to identify the contribution of flavincontaining monooxygenase 2 (FMO2) in AKICKD. Lentivirusmediated overexpression of FMO2 was performed in mice. Functional experiments were conducted using TGFßinduced tubular cell fibrogenesis and paracrine profibrotic factor secretion. Expression of FMO2 attenuated kidney injury induced by renal IRI, renal fibrosis, and immune cell infiltration into the kidneys. Overexpression of FMO2 not only effectively blocked TGF secretion in tubular cell fibrogenesis but also inhibited aberrant paracrine activation of profibrotic factors present in fibroblasts. FMO2 negatively regulated TGFßmediated SMAD2/3 activation by promoting the expression of SMAD ubiquitination regulatory factor 2 (SMURF2) and its nuclear translocation. During the transition from AKI to CKD, FMO2 modulated tubular cell fibrogenesis and paracrine secretion through SMURF2, thereby affecting the outcome of the disease.
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Injúria Renal Aguda , Insuficiência Renal Crônica , Humanos , Camundongos , Animais , Insuficiência Renal Crônica/metabolismo , Rim/patologia , Injúria Renal Aguda/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Células Epiteliais/metabolismo , Fibrose , Oxigenases de Função Mista/metabolismo , Oxigenases de Função Mista/farmacologia , Flavinas/metabolismo , Flavinas/farmacologia , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismoRESUMO
Fermented Chinese medicine has long been used. Amid the advance for preservation of experience, the connotation of fermented Chinese medicine has been enriched and improved. However, fermented Chinese medicine prescriptions generally contain a lot of medicinals. The fermentation process is complicated and the conventional fermentation conditions fail to be strictly controlled. In addition, the judgment of the fermentation end point is highly subjective. As a result, quality of fermented Chinese medicine is of great difference among regions and unstable. At the moment, the quality standards of fermented Chinese medicine are generally outdated and different among regions, with simple quality control methods and lacking objective safe fermentation-specific evaluation indictors. It is difficult to comprehensively evaluate and control the quality of fermented medicine. These problems have aroused concern in the industry and also affected the clinical application of fermented Chinese medicine. This article summarized and analyzed the application, quality standards, and the modernization of fermentation technology and quality control methods of fermented Chinese medicine and proposed suggestions for improving the quality standards of the medicine, with a view to improving the overall quality of it.
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Medicina Tradicional Chinesa , Padrões de Referência , Controle de Qualidade , FermentaçãoRESUMO
The effect of oxygen on the reduction of uranyl and photocorrosion of CdS remains a pressing issue when CdS is used as a photocatalyst for the removal of uranyl in uranium-containing wastewater. In this study, composites (CdS/PCN) were prepared by designing N-deficient g-C3N4 composite with CdS for efficient photocatalytic reduction of uranyl under aerobic condition. Meanwhile, a series of characterizations of the CdS/PCN composites were carried out by XRD, FT-IR, XPS, EDS and UV-vis. Surprisingly, the CdS/PCN not only showed very high photocatalytic reduction activity for uranyl under aerobic condition, but also the photocorrosion of CdS by oxygen and h+ was inhibited. With a starting uranium (VI) concentration of 20 ppm, the uranium (VI) removal efficiency could reach 97.33% (dark: 30 min, light: 10 min). Interestingly, the removal efficiency was better in air condition than in pure nitrogen or 30% oxygen atmosphere, i.e. a proper amount of oxygen has accelerated the reduction reaction, while excess oxygen weakened the reduction. Finally, a new mechanism of reduction of uranyl by CdS/PCN photocatalyst was given under aerobic condit ions. This work presents a novel strategy for reduction of U(VI) by photocatalysis and the inhibition of photocorrosion of photocatalysts under aerobic conditions.
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Urânio , Urânio/análise , Espectroscopia de Infravermelho com Transformada de Fourier , Catálise , Luz , Águas ResiduáriasRESUMO
Renal ischemia/reperfusion injury (IRI) is a significant clinical problem without effective therapy. Unbiased omics approaches may reveal key renal mediators to initiate IRI. S100-A8/A9 was identified as the most significantly upregulated gene and protein base on proteomic analysis and RNA sequencing during the early reperfusion stage. S100-A8/A9 levels were significantly increased 1 day after transplantation in patients with donation after brain death (DBD). S100-A8/A9 production was associated with CD11b+Ly6G+ CXCR2+ immunocytes infiltration. Administration of S100-A8/A9 blocker ABR238901 significantly alleviates renal tubular injury, inflammatory cell infiltration, and renal fibrosis after renal IRI. Mechanistically, S100-A8/A9 could promote renal tubular cell injury and profibrotic cytokine production via TLR4. In conclusion, our findings found that early activation of S100-A8/A9 in renal IRI and targeting S100-A8/A9 signaling alleviates tubular injury and inhibits inflammatory response and renal fibrosis, which may provide a novel target for the prevention and treatment of acute kidney injury.
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Injúria Renal Aguda , Traumatismo por Reperfusão , Humanos , Animais , Camundongos , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo , Proteômica , Rim/patologia , Traumatismo por Reperfusão/metabolismo , Injúria Renal Aguda/patologia , Fibrose , Camundongos Endogâmicos C57BLRESUMO
Renal ischemia-reperfusion injury (IRI) is mainly responsible for acute kidney injury for which there is no effective therapy. Accumulating evidence has indicated the important role of mitophagy in mitochondrial homeostasis under stress. OGG1 (8-oxoguanine DNA glycosylase) is known for functions in excision repair of nuclear and mitochondrial DNA. However, the role of OGG1 in renal IRI remains unclear. Herein, we identified OGG1, induced during IRI, as a key factor mediating hypoxia-reoxygenation-induced apoptosis in vitro and renal tissue damage in a renal IRI model. We demonstrated that OGG1 expression during IRI negatively regulates mitophagy by suppressing the PINK1/Parkin pathway, thereby aggravating renal ischemic injury. OGG1 knockout and pharmacological inhibition attenuated renal IRI, in part by activating mitophagy. Our results elucidated the damaging role of OGG1 activation in renal IRI, which is associated with the regulatory role of the PINK1/Parkin pathway in mitophagy.
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DNA Glicosilases , Traumatismo por Reperfusão , Humanos , Mitofagia , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , DNA Glicosilases/farmacologia , Proteínas Quinases/genética , Proteínas Quinases/metabolismoRESUMO
Ischemia/reperfusion injury (IRI) is prone to occur after kidney transplantation, leading to delayed graft function (DGF). MicroRNAs play a crucial role in the pathogenesis of ischemia/reperfusion-induced acute kidney injury, and miR-20a-5p was found to be the most significantly upregulated gene in a DGF patient cohort. However, the roles of microRNAs in transplanted kidneys remain largely unknown. In this study, we found that miR-20a-5p was upregulated in the kidneys of acute kidney injury mice and in patients with DGF. We identified early growth response-1 as a critical upstream target and verified the binding of early growth response-1 to a predicted sequence in the promoter region of the miR-20a-5p gene. Functionally, the miR-20a-5p mimic attenuated IRI and postischemic renal fibrosis, whereas the miR-20a-5p inhibitor delivery aggravated IRI and fibrosis. Importantly, delivery of the miR-20a-5p mimic or inhibitor in the donor kidneys attenuated or aggravated renal loss and structural damage in cold storage transplantation injury. Furthermore, our study identified miR-20a-5p as a negative regulator of acyl-CoA synthetase long-chain family member 4 (ACSL4) by targeting the 3' untranslated region of ACSL4 mRNA, thereby inhibiting ACSL4-dependent ferroptosis. Our results suggest a potential therapeutic application of miR-20a-5p in kidney transplantation through the inhibition of ACSL4-dependent ferroptosis.
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Injúria Renal Aguda , Ferroptose , MicroRNAs , Traumatismo por Reperfusão , Animais , Camundongos , MicroRNAs/genética , Rim/metabolismo , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/prevenção & controle , Injúria Renal Aguda/genética , Isquemia , Coenzima A Ligases/genéticaRESUMO
Renal ischemia-reperfusion injury (IRI) is the main cause of acute kidney injury (AKI), yet therapeutic approaches to alleviate IRI remain limited. PIM1 (provirus integration site for Moloney murine leukemia virus 1) is a constitutive serine threonine kinase that phosphorylates various substrates to regulate cell death and survival. However, the role of PIM1 in renal IRI remains unclear. This study aims to investigate the effect of PIM1 on renal IRI and explore its downstream regulatory mechanism. In this study, we inhibited or overexpressed PIM1 in mice and cultured proximal tubular cells, and then induced renal IRI model in vivo and hypoxia reoxygenation (HR) model in vitro. Renal function, renal structure injuries and cellular death were assessed to reflect the extent of IRI. The expression of PIM1 and the levels of ASK1, MAPK and their phosphorylated forms were detected by immunoblot. RNA sequencing of kidney cortex was performed to analyze downstream pathway of PIM1 in renal IRI. The results showed that PIM1 expression was significantly upregulated in renal IRI mouse model and in renal tubular cell HR model. AZD1208 (a PIM1 inhibitor) aggravated renal IRI, while PIM1 overexpression ameliorated renal IRI. This was involved in the regulation of the ASK1-MAPK pathway. Moreover, results demonstrated that ASK1 was a downstream target of PIM1 by administering Selonsertib (an inhibitor of ASK1 activity), and inhibiting ASK1 alleviated cell death after HR in PIM1 knockdown cells by reducing JNK/P38 activation. In conclusion, this study elucidated the protective effect of PIM1 on renal IRI, and the underlying mechanism may be related to ASK1-JNK/P38 signaling pathway. Taken together, PIM1 may be a potential therapeutic target for renal IRI.
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Nefropatias , Traumatismo por Reperfusão , Camundongos , Animais , Transdução de Sinais , Rim/metabolismo , Traumatismo por Reperfusão/metabolismo , Nefropatias/metabolismo , Sistema de Sinalização das MAP Quinases , ApoptoseRESUMO
Histone deacetylase (HDAC) 6 exists exclusively in cytoplasm and deacetylates cytoplasmic proteins such as α-tubulin. HDAC6 dysfunction is associated with several pathological conditions in renal disorders, including UUO-induced fibrotic kidneys and rhabdomyolysis-induced nephropathy. However, the role of HDAC6 in ischemic acute kidney injury (AKI) and the mechanism by which HDAC6 inhibition protects tubular cells after AKI remain unclear. In the present study, we observed that HDAC6 was markedly activated in kidneys subjected to ischemia- and cisplatin (cis)-induced AKI treatment. Pharmacological inhibition of HDAC6 alleviated renal impairment and renal tubular damage after ischemia and cisplatin treatment. HDAC6 dysfunction was associated with decreased acetylation of α-tubulin at the residue of lysine 40 and autophagy. HDAC6 inhibition preserved acetyl-α-tubulin-enhanced autophagy flux in AKI and cultured tubular cells. Genetic ablation of the renal tubular (RT) Atg7 gene or pharmacological inhibition of autophagy suppressed the protective effects of HDAC6. Taken together, our study indicates that HDAC6 contributes to ischemia- and cisplatin-induced AKI by inhibiting autophagy and the acetylation of α-tubulin. These results suggest that HDAC6 could be a potential target for ischemic and nephrotoxic AKI.
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Injúria Renal Aguda , Cisplatino , Desacetilase 6 de Histona , Isquemia , Humanos , Injúria Renal Aguda/genética , Injúria Renal Aguda/metabolismo , Autofagia/genética , Cisplatino/efeitos adversos , Desacetilase 6 de Histona/genética , Desacetilase 6 de Histona/metabolismo , Isquemia/genética , Isquemia/metabolismo , Tubulina (Proteína)/metabolismoRESUMO
Background and objective: Depression is a complex neuropsychiatric disease with extensive morbidity. Its pathogenesis remains unclear, and it is associated with extremely low rates of cure and complete remission. It is vital to study the pathogenesis of depression to develop effective treatments. This study aimed to explore the therapeutic effects and mechanisms of fecal microbiota transplantation (FMT) for the treatment of depression in rats. Methods: Thirty Sprague-Dawley (SD) rats were randomly divided into three groups: control, chronic unpredictable mild stress (CUMS) to model depression, and CUMS+FMT. For the CUMS and CUMS+FMT groups, after CUMS intervention (four weeks), the rats were given normal saline or FMT (once/week for three weeks), respectively. Behavior, colonic motility, 16S rDNA amplicon sequencing, and untargeted metabolomics on fecal samples were compared between the three rat groups. The following markers were analyzed: 5-hydroxytryptamine (5-HT), gamma-aminobutyric acid (GABA), glutamate (Glu), and brain-derived neurotrophic factor (BDNF) levels in the hippocampus; glucagon-like peptide 1 (GLP-1), lipopolysaccharide (LPS), and interleukin (IL)-6 levels in the serum; and GLP-1, GLP-1 receptor (GLP-1R), and serotonin 4 receptor (5-HT4R) levels in colonic tissues. Results: FMT improved symptoms of depression and colonic motility in rats exposed to CUMS. The expression levels of 5-HT, GABA, BDNF, and other biochemical indices, significantly differed among the three groups. Meanwhile, the intestinal microbiota in the CUMS+FMT group was more similar to that of the control group with a total of 13 different fecal metabolites. Conclusion: FMT exerted antidepressant effects on CUMS-induced depression in rats, and the mechanism involved various neurotransmitters, inflammatory factors, neurotrophic factors, and glucagon-like peptides.
Assuntos
Depressão , Transplante de Microbiota Fecal , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Depressão/etiologia , Depressão/metabolismo , Depressão/terapia , Peptídeo 1 Semelhante ao Glucagon , Ratos , Ratos Sprague-Dawley , Serotonina , Estresse Psicológico/terapia , Ácido gama-AminobutíricoRESUMO
Acute kidney injury (AKI) is a critical and severe clinical disease caused by a variety of factors. Toll-like receptors (TLRs) play a crucial role in pathogenesis of AKI. Radioprotective 105 kDa protein (RP105) is a member of the TLR family, but the role of RP105 in AKI is unknown. In this study, we overexpressed RP105 in renal tissue and cultured proximal tubular cells in which we then induced ischemic and septic AKI. Renal structure injuries were examined by hematoxylin eosin staining, while renal function was assessed by measuring serum blood urea nitrogen (BUN) and creatinine (SCr) levels. The TUNEL assay was used to detect apoptosis induced changes in the expression of RP105, and nuclear factor κB (NF-κB) in renal tissue detected by Western blot. Inflammatory cytokines including iNOS, IL-1ß, IL-6, and TNF-α were detected by quantitative real-time PCR. The inflammatory indicators, F4/80 and MPO, were identified by IHC staining. The results showed that expression of the TLR4/NF-kB signaling pathway was enhanced in renal ischemia-reperfusion injury and septic renal injury, and that overexpression of RP105 in renal tissue alleviated ischemic and septic AKI. Moreover, RP105 gene delivery was associated with reduced renal inflammatory cells infiltration and inflammatory cytokines after AKI. RP105 overexpression also inhibited nuclear translocation of NF-κB after AKI in both in vitro and in vivo, and blunted the interaction between Myeloid Differentiation factor 2 (MD2) and TLR4. These results indicated that RP105 protected against renal ischemic and septic AKI injury by suppressing inflammatory responses mediated by TLR4 signaling pathways. This study suggests that the anti-inflammatory roles of RP105 have potential for preventing and treating renal ischemic and septic AKI.