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INTRODUCTION: It is crucial to utilize combination therapy for immunoglobulin A nephropathy (IgAN) patients to reduce proteinuria and maintain stable kidney function. We demonstrate the safety and efficacy of low-dose spironolactone in the management of IgAN patients. METHODS: Adult IgAN patients treated with spironolactone were evaluated. Patients were separated into two categories according to whether 24-h proteinuria was reduced by more than 20% after 2 months of spironolactone treatment compared to baseline levels. RESULTS: Eighty-eight patients were analyzed and 24-h proteinuria decreased from 0.93 g to 0.70 g (p < 0.001) after 2 months of treatment with spironolactone, accompanied by a slight decrease in eGFR from 75.7 to 73.9 mL/min/1.73 m2 (p = 0.033). Intriguingly, 47 patients in the effective mineralocorticoid receptor antagonist (MRA) group showed less endocapillary hypercellularity (p = 0.040). In the ineffective group, 18 patients discontinued MRA treatment because 24-h proteinuria increased from 0.83 g to 1.04 g, while the other 23 patients continued with spironolactone and proteinuria decreased to 0.57 g in the sixth month (p = 0.001). Furthermore, 12 patients with persistent high proteinuria during prednisone therapy were added with spironolactone. 24-proteinuria was dropped from 0.95 g to 0.73 g at the second month and to 0.50 g at the sixth month. CONCLUSIONS: In our study, we confirmed spironolactone's efficacy in reducing urine protein excretion in IgA nephropathy patients within 2 months of treatment. However, response varied among patients, with those showing endocapillary proliferation (E1) in renal biopsies having poor spironolactone responsiveness. Administering MRAs to patients with eGFR over 30 mL/min did not result in hyperkalemia, indicating the treatment's safety.
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Glomerulonefrite por IGA , Antagonistas de Receptores de Mineralocorticoides , Proteinúria , Espironolactona , Humanos , Glomerulonefrite por IGA/tratamento farmacológico , Espironolactona/uso terapêutico , Espironolactona/efeitos adversos , Masculino , Adulto , Feminino , Estudos Retrospectivos , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Antagonistas de Receptores de Mineralocorticoides/efeitos adversos , Proteinúria/tratamento farmacológico , Pessoa de Meia-Idade , Resultado do Tratamento , Taxa de Filtração GlomerularRESUMO
INTRODUCTION: There are increasing case reports on de novo or relapsing IgA nephropathy (IgAN) following SARS-CoV-2 vaccines, although the follow-up information on renal outcomes in IgAN patients post-SARS-CoV-2 vaccination is limited. In this study, we evaluated the renal outcomes of IgAN patients following inactivated vaccines. METHODS: We investigated the change in eGFR, proteinuria and hematuria in 113 primary IgAN patients post-vaccination. Worsening proteinuria was defined as an increase in proteinuria by more than 0.5 times and proteinuria > 1 g/d. Univariate and multivariable logistic regression analysis were used to evaluate possible predictors of worsening proteinuria. We then compared the renal outcomes of vaccinated patients after 6 months with 101 unvaccinated patients who were followed during the same period. RESULTS: A 2.54% (0.64, 8.61) decrease in renal function was observed in post-vaccination patients. Subgroup analysis revealed a significant decrease in eGFR in patients with 30 ≤ eGFR < 60 (mL/min/1.73 m2) post second SARS-CoV-2 dose (n = 18, p = 0.01). In addition, 10 individuals displayed worsening proteinuria post-vaccination, with the proteinuria subsequently ameliorating significantly after 6-month. Multivariate analysis showed that higher eGFR levels was an independent protective factor for worsening proteinuria. The renal outcome tended towards a decrease in eGFR in vaccinated patients after 6 months follow-up, although the difference was not significant (p = 0.06). CONCLUSION: Kidney function in IgAN patients tended to worsen after SARS-CoV-2 vaccination, particularly those with initial poor kidney function. This pattern of disease flare appears to be clinically mild, and further research is needed to determine whether the impact on kidney function is long-term.
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COVID-19 , Glomerulonefrite por IGA , Humanos , Glomerulonefrite por IGA/complicações , Vacinas contra COVID-19/efeitos adversos , SARS-CoV-2 , COVID-19/prevenção & controle , COVID-19/complicações , Rim , Proteinúria/etiologiaRESUMO
The development and formation of mammalian blood vessels are closely related to the regulation of signal transduction pathways. Klotho/AMPK and YAP/TAZ signaling pathways are closely related to angiogenesis, but the internal relationship between them is not clear. In this study, we found that Klotho heterozygous deletion mice (Klotho+/- mice) had obvious thickening of the renal vascular wall, obvious enlargement of vascular volume, and significant proliferation and pricking of vascular endothelial cells. Western blot showed that the expression levels of total YAP protein, p-YAP protein (Ser127 and Ser397), p-MOB1, MST1, LATS1, and SAV1 in renal vascular endothelial cells were significantly lower in Klotho+/- mice than in wild-type mice. Knockdown of endogenous Klotho in HUVECs accelerated their ability to divide and form vascular branches in the extracellular matrix. Meanwhile, the results of CO-IP western blot showed that the expression of LATS1 and p-LATS1 interacting with AMPK protein decreased significantly, and the ubiquitination level of YAP protein also decreased significantly in vascular endothelial cells of kidney tissue of Klotho+/- mice. Subsequently, continuous overexpression of exogenous Klotho protein in Klotho heterozygous deficient mice effectively reversed the abnormal renal vascular structure by weakening the expression of the YAP signal transduction pathway. Therefore, we confirmed that Klotho and AMPKα proteins were highly expressed in vascular endothelial cells of adult mouse tissues and organs; this resulted in a phosphorylation modification of YAP protein, closed the activity of the YAP/TAZ signal transduction pathway, and inhibited the growth and proliferation of vascular endothelial cells. When Klotho was absent, the phosphorylation modification of YAP protein by AMPKα was inhibited, resulting in the activation of the YAP/TAZ signal transduction pathway and finally inducing the excessive proliferation of vascular endothelial cells.
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Proteínas Quinases Ativadas por AMP , Proteínas Adaptadoras de Transdução de Sinal , Proteínas Klotho , Animais , Camundongos , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Proliferação de Células/genética , Células Endoteliais/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais/genética , Fatores de Transcrição/metabolismo , Proteínas de Sinalização YAP/metabolismo , Proteínas Klotho/genéticaRESUMO
AIM: Tenascin-C (TNC), a non-structural extracellular matrix glycoprotein, is transiently expressed during development or after injury, playing an important role in injury and repair process. The potential role of TNC in the pathogenesis of IgA nephropathy (IgAN) remains to be clarified. METHODS: Immunohistochemistry staining for TNC was conducted on paraffin-embedded slices from renal biopsies of 107 IgAN patients, and correlation analysis was made between mesangial TNC expression and clinic-pathological parameters. In situ hybridization for TNC mRNA was further performed to figure out the cells that express TNC within glomeruli. In vitro experiments were also carried out on mouse mesangial cells (SV40 MES13) to elucidate the effect of TNC on mesangial cells. RESULTS: TNC was expressed in the mesangial area of IgAN, as well as in fibrotic regions. Correlation analysis showed that higher mesangial TNC was associated with higher level of proteinuria, lower estimated glomerular filtration rate and more serious pathological lesions (MEST score). In situ hybridization revealed that abundant TNC mRNA expression was observed in the affected glomeruli of IgAN, but not in minimal change disease. Moreover, TNC mRNA co-localized with PDGFRß mRNA, but not with PODXL mRNA, suggesting that TNC mRNA was expressed in the mesangial cells within glomeruli in IgAN. In vitro experiments showed that exogenous TNC promoted matrix protein production and mesangial cell proliferation, which was attenuated by an epidermal growth factor receptor inhibitor. CONCLUSION: Taken together, these results suggest that mesangial cell-derived TNC contributes to mesangial matrix expansion and mesangial cell proliferation, which is a potential therapeutic target in IgAN.
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Glomerulonefrite por IGA , Células Mesangiais , Animais , Proliferação de Células , Matriz Extracelular/metabolismo , Glomerulonefrite por IGA/patologia , Humanos , Células Mesangiais/patologia , Camundongos , Tenascina/genética , Tenascina/farmacologiaRESUMO
BACKGROUND/AIMS: We aimed to determine if soluble α-klotho level was an indicator of chronic kidney disease (CKD) progression and whether α-klotho interacted with aldosterone during the course of further renal damage. METHODS: 112 adults with stages 1-5 CKD were enrolled into our cohort study. All of the patients were followed up for 6 years (from January 2010 to December 2015). Serum soluble α-klotho and aldosterone were measured at baseline and at 1.5-years follow-up. The primary outcome was the initiation of renal replacement therapy (RRT) and the secondary outcome was the occurrence of cardio-cerebrovascular events. Long-term progression to RRT and cardio-cerebrovascular events in patients was analyzed with a risk-adjusted Cox proportional hazards regression model. Adjustment included age, gender, eGFR, mean arterial pressure, 24-h protein excretion and the change in α-klotho level from baseline at 1.5-years follow-up. RESULTS: Baseline circulating α-klotho levels were positively associated with baseline estimated glomerular filtration rate (eGFR; r = 0.224, p = 0.017), but not age, calcium, phosphate, or parathyroid hormone levels. The change in α-klotho level from baseline at 1.5-years follow-up (p = 0.002) was independently associated with renal replace treatment (RRT) initiation after adjustment for age, gender, eGFR, mean arterial pressure, and 24-h protein excretion in Cox regression analysis. Aldosterone levels were positively associated with CKD stage, and were inversely correlated with circulating α-klotho levels. CONCLUSION: The change in concentration of soluble α-klotho during the 1.5-years follow-up was an indicator of CKD progression. Renal damage associated with a reduction of α-klotho may involve the upregulation of plasma aldosterone. Future studies are needed to validate our findings, and to investigate the underlying mechanism by which α-klotho and aldosterone may cause renal damage.
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Aldosterona/sangue , Glucuronidase/sangue , Insuficiência Renal Crônica/diagnóstico , Aldosterona/metabolismo , Progressão da Doença , Seguimentos , Taxa de Filtração Glomerular , Glucuronidase/metabolismo , Humanos , Proteínas Klotho , Insuficiência Renal Crônica/etiologia , Insuficiência Renal Crônica/terapia , Terapia de Substituição RenalRESUMO
OBJECTIVE: Adult immunoglobulin A vasculitis (IgAV) is documented to be associated with more renal involvement and poorer renal outcomes compared to children, but adult IgAV nephritis (IgAV-N) data are rather limited. The present study aimed to describe the characteristics of adult IgAV-N and investigate the long-term prognostic factors. METHODS: Clinical and morphological data from 106 adult patients with biopsy-proven IgAV-N and follow-up data from 94 patients in a single Chinese center were analyzed in this retrospective study. Median follow-up time interval was 102 months. RESULTS: The median age of patients with IgAV-N at biopsy was 38 (IQR 24-53) years, and 52.8% were male. The median blood pressure was 126/80 mmHg, and 25.5% of patients were hypertensive at baseline. The median initial proteinuria was 1.4 (IQR 0.7-2.2) g/day and estimated glomerular filtration rate (eGFR) was 103 (IQR 84-121) mL/min/1.73 m2. The median time interval of onset to biopsy was 8 (IQR 3-40) weeks. In biopsy, the median percentage of global sclerosis was 5.9% (IQR 0.0-13.8), whereas 45.3% of patients had interstitial fibrosis and tubular atrophy. Further, during follow-up, 7.4% patients died, 4.3% patients progressed to endstage kidney disease (ESKD), and 6.4% patients developed > 30% eGFR reduction from baseline. Multivariate Cox proportional analyses revealed hypertension (HTN) history and > 10% global sclerosis at presentation were independent prognostic factors for poor outcome. CONCLUSION: The present adult IgAV-N cohort revealed a relatively young onset age, and lower incidence of nephrotic syndrome and ESKD. Moreover, nonimmune factors such as history of HTN and renal chronic histological lesions in biopsy played a crucial role in prognosis of IgAV-N.
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Hipertensão , Vasculite por IgA , Falência Renal Crônica , Nefrite , Criança , Humanos , Adulto , Masculino , Adulto Jovem , Pessoa de Meia-Idade , Feminino , Vasculite por IgA/complicações , Estudos Retrospectivos , Esclerose/complicações , Nefrite/etiologia , Nefrite/patologia , Prognóstico , Falência Renal Crônica/etiologia , Hipertensão/complicações , Imunoglobulina ARESUMO
Since Alzheimer's disease (AD) is a complex and multifactorial neuropathology, the discovery of multi-targeted inhibitors has gradually demonstrated greater therapeutic potential. Neurofibrillary tangles (NFTs), the main neuropathologic hallmarks of AD, are mainly associated with hyperphosphorylation of the microtubule-associated protein Tau. The overexpression of GSK3ß and DYRK1A has been recognized as an important contributor to hyperphosphorylation of Tau, leading to the strategy of using dual-targets inhibitors for the treatment of this disorder. ZDWX-12 and ZDWX-25, as harmine derivatives, were found good inhibition on dual targets in our previous study. Here, we firstly evaluated the inhibition effect of Tau hyperphosphorylation using two compounds by HEK293-Tau P301L cell-based model and okadaic acid (OKA)-induced mouse model. We found that ZDWX-25 was more effective than ZDWX-12. Then, based on comprehensively investigations on ZDWX-25 in vitro and in vivo, 1) the capability of ZDWX-25 to show a reduction in phosphorylation of multiple Tau epitopes in OKA-induced neurodegeneration cell models, and 2) the effect of reduction on NFTs by 3xTg-AD mouse model under administration of ZDWX-25, an orally bioavailable, brain-penetrant dual-targets inhibitor with low toxicity. Our data highlight that ZDWX-25 is a promising drug for treating AD.
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Doença de Alzheimer , Camundongos , Animais , Humanos , Doença de Alzheimer/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Células HEK293 , Proteínas tau/metabolismo , Fosforilação , Ácido Okadáico/metabolismo , Ácido Okadáico/farmacologia , Ácido Okadáico/uso terapêutico , Modelos Animais de DoençasRESUMO
WNK is a serine/threonine kinase. Mutation in WNK1 or WNK4 kinase results in pseudohypoaldosteronism type II (PHA II) featuring hypertension, hyperkalemia and metabolic acidosis. Sodium chloride cotransporter (NCC) is known to be regulated by phosphorylation and trafficking. Dietary salt and hormonal stimulation, such as aldosterone, also affect the regulation of NCC. We have previously reported that WNK4 inhibits NCC protein expression. To determine whether dietary salt affects NCC abundance through WNK4-mediated mechanism, we investigated the effects of dietary salt change with or without aldosterone infusion (1 mg/kg/day) on NCC and WNK4 expression in rats. We found that high-salt (HS, 4% NaCl) diet significantly inhibits NCC mRNA expression and protein abundance while enhancing WNK4 mRNA and protein expression, whereas low-salt (LS, 0.07% NaCl) diet increases NCC mRNA expression and protein abundance while reducing WNK4 expression. We also found that aldosterone infusion in HS-fed rats increases NCC mRNA expression and protein abundance, but decreases WNK4 expression. Administration with spironolactone (0.1 g/kg/day) in LS-fed rats decreases NCC mRNA expression and protein abundance while increasing WNK4 expression. We further showed that ERK1/2 phosphorylation was increased in HS-fed rats, but decreased in LS-fed rats. In HEK293 cells, over-expressed WNK4 increases ERK1/2 phosphorylation, whereas knockdown of WNK4 expression decreases ERK1/2 phosphorylation. Aldosterone treatment for 3 h decreases ERK1/2 phosphorylation. These data suggest that dietary salt change affects NCC protein abundance in an aldosterone-dependent mechanism likely via the WNK4-ERK1/2-mediated pathway.
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Aldosterona/fisiologia , Sistema de Sinalização das MAP Quinases/fisiologia , Proteínas Serina-Treonina Quinases/fisiologia , Pseudo-Hipoaldosteronismo/fisiopatologia , Simportadores de Cloreto de Sódio/biossíntese , Cloreto de Sódio na Dieta/administração & dosagem , Aldosterona/farmacologia , Animais , Células HEK293 , Humanos , RNA Mensageiro/metabolismo , RatosRESUMO
Background: Keyin pill (KP), a patented medicine in China, is used to treat psoriasis. However, KP has been reported to have liver toxicity, but its toxic substance basis and underlying mechanisms remain unclear. Therefore, this study aimed to explore the pharmacological mechanisms and components of KP-induced liver injury through animal experiments, UPLC-QTOF/MS combined with network pharmacology. Methods: Firstly, based on the immune stress mouse model, liver function parameters and hematoxylin-eosin (H&E) staining were detected to investigate KP-induced liver injury. The UPLC-QTOF/MS method was used to identify the components of KP. CTD database and literature mining were further applied to screen nonliver protective components. Subsequently, the nonliver protective components and their corresponding targets and targets of hepatotoxicity were analyzed by the method of network pharmacology. Finally, key targets from networked pharmacology were examined by the enzyme-linked immunosorbent assay (ELISA) and molecular docking. Results: Our results indicated that KP had hepatotoxicity in male Kunming mice, which could favor hepatocyte necrosis and infiltration of inflammatory cells. A total of 70 nonliver protective compounds were identified and screened. The results of network pharmacology illustrated that methoxsalen, obacunone, limonin, and dictamnine might be the main compounds that caused liver damage. The potential hepatotoxicity mechanisms of KP might be through the IL17 and apoptosis pathways to regulate IL6, TNFα, CASP3, and CASP8 targets, thereby causing inflammation, excessive release of factors, and hepatocyte necrosis. The results of the ELISA experiments indicated that KP could increase the release of IL6 and TNFα inflammatory factors in liver tissues. Molecular docking suggested that methoxsalen, obacunone, limonin, and dictamnine had moderate binding ability with CASP3 and CASP8. Conclusion: In this study, the material basis and potential pharmacological mechanisms of KP-induced liver injury were preliminarily explored. Our research provides the initial theoretical basis for reducing the toxicity of KP.
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Klotho expression abnormalities induces kidney injury and chronic kidney disease, however, the underlying mechanism remains unclear. Here, Klotho+/- mice and wild-type mice were treated with low-dose bovine serum albumin (BSA). Pathological examination demonstrated that the area of glomerular collagen deposition and fibrosis in BSA-Kl-/+ mice was significantly larger than that in BSA-WT mice. The serum levels of superoxide dismutase, malondialdehyde, creatinine, and urea in BSA-Kl-/+ mice were significantly increased. Sequencing of gut microbiota 16S rRNA v3-v4 region indicated that BSA-Kl-/+ mice showed a significantly higher relative abundance of the genera Dubosiella, Akkermansia, Alloprevotella, and Lachnospiraceae and a significantly lower relative abundance of the genera Allobaculum and Muribaculaceae than BSA-WT mice. KEGG analysis revealed that the metabolic pathways of signal transduction, xenobiotic biodegradation and metabolism, and lipid metabolism increased significantly in BSA-Kl-/+ mice. Flow cytometry showed that the proportion of CD68+/CD11b+ cells in the peripheral blood was significantly higher in BSA-KL-/+ mice than that in BSA-WT mice. qPCR and western blot suggested that Klotho and Nrf2 expression in MΦ1 cells of BSA-KL-/+ mice was significantly decreased. Thus, the findings suggest during the immune activation and chronic inflammation induced by the gut microbiota imbalance in Klotho-deficient mice treated to BSA, disrupted expression of proteins in the Nrf2/NF-κB signaling pathway in monocyte-derived macrophage M1 cells leads to the aggravation of inflammation and kidney injury.
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Microbioma Gastrointestinal/imunologia , Proteínas Klotho/fisiologia , Ativação de Macrófagos , Insuficiência Renal Crônica/etiologia , Animais , Masculino , Camundongos , Soroalbumina BovinaRESUMO
Patients with IgA vasculitis (IgAV), an immune complex-mediated disease, may exhibit kidney involvement-IgAV with nephritis (IgAVN). The kidney-biopsy histopathologic features of IgAVN are similar to those of IgA nephropathy, but little is known about histopathologic disease severity based on the interval between purpura onset and diagnostic kidney biopsy. We assessed kidney histopathology and clinical and laboratory data in a cohort of adult patients with IgAVN (n = 110). The cases were grouped based on the interval between the onset of purpura and kidney biopsy: Group 1 (G1, <1 month, n = 14), Group 2 (G2, 1-6 months, n = 58), and Group 3 (G3, >6 months, n = 38). Glomerular leukocytes were more common in G1 than in the other groups (p = 0.0008). The proportion of neutrophils among peripheral-blood leukocytes was the highest in the patients biopsied within a month after onset of purpura (G1: 71 ± 8%). In the patients with an interval >6 months, the neutrophil proportion was lower, 60%. Moreover, the glomerular mesangial proliferation score correlated with the serum total IgA concentration (p = 0.0056). In conclusion, IgAVN patients biopsied <1 month from purpura onset showed an elevated percentage of blood neutrophils and glomerular leukocytes, consistent with an acute-onset inflammatory reaction. In all IgAVN patients, the mesangial proliferation score correlated with the serum IgA level.
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RATIONALE & OBJECTIVE: We aimed to explore the associated factors of endothelial injury in chronic kidney disease (CKD) and the relationship between endothelial dysfunction and CKD prognosis. STUDY DESIGN: A prospective observational cohort study. SETTING & PARTICIPANTS: 77 adults with CKD stages 1-5 were enrolled January 2010 to December 2010 and followed up until December 2015. EXPOSURE: Serum asymmetric dimethylarginine (ADMA) level at baseline, α-klotho, sodium-phosphorus synergistic transporter, and dimethylarginine-dimethylamine hydrolase expression in kidney biopsy samples. OUTCOME: Initiation of kidney replacement therapy (KRT). ANALYTICAL APPROACH: Kaplan-Meier analysis was used for evaluation of the incidence rate of KRT. All tests were 2 tailed, and statistical significance was defined as P < 0.05. RESULTS: Mean serum ADMA level of 77 patients was 64.3 ± 34.6 ng/mL. ADMA level increased with CKD stages (P = 0.06) and declining kidney function (r = -0.267; P = 0.02). The expression of α-klotho in kidney biopsy specimens also decreased. Median follow-up time was 56 (interquartile range, 50.5-62) months. Kaplan-Meier analyses showed that during a total follow-up of 6 years, the incidence of KRT initiation in the high-ADMA group was significantly higher than that in the low group (35.9% vs 13.2%; P = 0.03). ADMA level was negatively correlated with α-klotho (r = -0.233; P = 0.04) and positively correlated with phosphorus level (r = 0.243; P = 0.04). The expression of sodium-phosphorus synergistic transporter in kidney tubules, which promoted phosphorus reabsorption, and the expression of dimethylarginine-dimethylamine hydrolase isoform 1, which regulated ADMA, were decreased. Correlation analysis also showed that ADMA level decreased while age increased at baseline (r = -0.292; P = 0.01). LIMITATIONS: Small sample size with limited longer-term follow-up. CONCLUSIONS: Serum ADMA levels increased as kidney function declined, and high serum ADMA level was associated with incident kidney failure. Low tissue α-klotho and high levels of plasma phosphorus or tissue expression of type II sodium/phosphate cotransporter in the kidney are associated with higher circulating ADMA levels, suggesting that they may be involved in the pathogenesis of endothelial dysfunction in patients with CKD.
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Henoch-Schonlein purpura nephritis (HSPN) is a common glomerulonephritis secondary to Henoch-Schonlein purpura (HSP) that affects systemic metabolism. Currently, there is a rarity of biomarkers to predict the progression of HSPN. This work sought to screen metabolic markers to predict the progression of HSPN via serum-urine matched metabolomics. A total of 90 HSPN patients were enrolled, including 46 HSPN (+) patients with severe kidney damage (persistent proteinuria >0.3 g/day) and 44 HSPN (-) patients without obvious symptoms (proteinuria < 0.3 g/day). Untargeted metabolomics was determined by liquid chromatography-quadrupole time-of-flight mass spectrometry (LC-Q/TOF-MS). A total of 38 and 50 differential metabolites were, respectively, identified in serum and urine from the comparison between HSPN (+) and HSPN (-) patients. Altered metabolic pathways in HSPN (+) mainly included glycerophospholipid metabolism, pyruvate metabolism, and citrate cycle. A panel of choline and cis-vaccenic acid gave areas under the curve of 92.69% in serum and 72.43% in urine for differential diagnosis between HSPN (+) and HSPN (-). In addition, the two metabolites showed a significant association with clinical indices of HSPN. These results suggest that serum-urine matched metabolomics comprehensively characterized the metabolic differences between HSPN (+) and HSPN (-), and choline and cis-vaccenic acid could serve as biomarkers to predict HSPN progression.
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BACKGROUND: Aldosterone plays an important role in fibrosis. Recent studies showed that Na(+)-H(+) exchanger isoform 1 (NHE1) is involved in mineralocorticoid-induced organ fibrosis. In this study, we examined the role of NHE1 in aldosterone-induced fibronectin accumulation in rat mesangial cells and the signaling pathway involved. METHODS: We detected the expression of mineralocorticoid receptor and 11beta-hydroxysteroid dehydrogenase 2 in rat glomeruli by immunochemistry and Western blot. Then the eukaryotic vectors of shRNA with insert targeting on NHE1 were successfully constructed and transfected into rat mesangial cells. The mRNA was quantified by real-time PCR. We measured the protein abundance of NHE1, ERK1/2 and phosphor-ERK1/2 by Western blot and the level of fibronectin by ELISA. RESULTS: First we demonstrated the local action of aldosterone on rat glomeruli in vivo. Then, after exposure to aldosterone, the NHE1 protein abundance was found increased in rat mesangial cells. Aldosterone treatment markedly increased the fibronectin level, which can be reduced by PD98059, spironolactone and shRNA-NHE1. PD98059 substantially reduced the aldosterone-induced NHE1 expression, while the knocking down of NHE1 did not alter aldosterone-stimulated phospho-ERK1/2 stimulation. CONCLUSION: The present study suggests that NHE1 may play an important role in aldosterone-mediated fibronectin accumulation in rat mesangial cells via the ERK1/2 pathway.
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Aldosterona/fisiologia , Fibronectinas/biossíntese , Células Mesangiais/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/fisiologia , Trocadores de Sódio-Hidrogênio/fisiologia , Animais , Células Cultivadas , Masculino , Isoformas de Proteínas/fisiologia , Ratos , Ratos Sprague-DawleyRESUMO
Trimethylamine N-oxide (TMAO) leads to the development of cardiovascular and chronic kidney diseases, but there are currently no potent drugs that inhibit the production or toxicity of TMAO. In this study, high-fat diet-fed ApoE-/- mice were treated with finasteride, ranitidine, and andrioe. Subsequently, the distribution and quantity of gut microbiota in the faeces of the mice in each group were analysed using 16S rRNA sequencing of the V3+V4 regions. Pathological examination confirmed that both ranitidine and finasteride reduced atherosclerosis and renal damage in mice. HPLC analysis also indicated that ranitidine and finasteride significantly reduced the synthesis of TMAO and the TMAO precursor delta-Valerobetaine in their livers. The 16S rRNA sequencing showed that all 3 drugs significantly increased the richness and diversity of gut microbiota in the model mice. Bioinformatic analysis revealed that the faeces of mice treated with ranitidine and finasteride, had significant increases in the number of microbes in the families g_Helicobacter, f_Desulfovibrionaceae, Mucispirillum_schaedleri_ASF457, and g_Blautia, whereas the relative abundances of microbes in the families Enterobacter_sp._IPC1-8 and g_Bacteroides were significantly reduced. The microbiota metabolic pathways, such as nucleotide and cofactor and vitamin metabolism were also significantly increased, whereas the activities of metabolic signalling pathways related to glycan biosynthesis and metabolism and cardiovascular diseases were significantly reduced. Therefore, our study indicates that in addition to their known pharmacological effects, ranitidine and finasteride also exhibit potential cardiovascular and renal protective effects. They inhibit the synthesis and metabolism of TMAO and delay the deposition of lipids and endotoxins through improving the composition of the gut microbiota.
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Finasterida/uso terapêutico , Rim/metabolismo , Metilaminas/metabolismo , Ranitidina/uso terapêutico , Animais , Aterosclerose/tratamento farmacológico , Aterosclerose/metabolismo , Cromatografia Líquida de Alta Pressão , Microbioma Gastrointestinal/efeitos dos fármacos , Rim/efeitos dos fármacos , Nefropatias/tratamento farmacológico , Nefropatias/metabolismo , Masculino , Camundongos , RNA Ribossômico 16S/metabolismoRESUMO
Aldosterone has an important role in the progression of renal fibrosis. In the present study, the concentration of aldosterone and klotho (KL) in the serum of patients with chronic kidney disease (CKD) were analyzed. A negative correlation was observed between aldosterone and KL, suggesting that KL may serve a protective role in CKD. Subsequently, an aldosteroneinduced CKD mouse model was established using a single nephrectomy and subcutaneous osmotic pump with aldosterone and 1% highsalt drinking water. It was demonstrated that fibronectin 1 (Fn1) expression levels were higher in high aldosterone mice, whereas KL expression levels were low. In addition, the results demonstrated that histone deacetylase 1 (HDAC1) protein expression levels were upregulated in the renal distal convoluted tubules of high aldosterone mice, whereas acetylated H3K9 (H3K9Ac) was significantly downregulated. To determine the transcriptional activation status, chromatin immunoprecipitation polymerase chain reaction (PCR) was used to validate binding of H3K9Ac to the KL gene promoter site. It was revealed that the binding product of the KL promoter could be PCRamplified at the H3K9Ac site from wildtype and low aldosterone mice; however, amplification of the binding product was not observed in high aldosterone mice. In conclusion, aldosterone significantly inhibited H3K9 acetylation by upregulating HDAC1 protein expression levels in the renal distal convoluted tubule cells, resulting in its inability to bind to the KL promoter, loss of transcription of the KL gene and increased expression of the renal fibrosis gene, Fn1.
Assuntos
Glucuronidase/genética , Histona Desacetilase 1/metabolismo , Rim/metabolismo , Rim/patologia , Transcrição Gênica , Acetilação , Adulto , Idoso , Idoso de 80 Anos ou mais , Aldosterona , Animais , Regulação para Baixo , Feminino , Fibronectinas/metabolismo , Fibrose , Glucuronidase/metabolismo , Histonas/metabolismo , Humanos , Túbulos Renais/metabolismo , Túbulos Renais/patologia , Proteínas Klotho , Lisina/metabolismo , Masculino , Camundongos , Pessoa de Meia-Idade , Insuficiência Renal Crônica/genética , Regulação para Cima/genéticaRESUMO
BACKGROUND/AIMS: It is widely accepted that a possible etiopathogenic factor associated with IgA nephropathy is the glycosylation of IgA1 molecule O-glycans. The present study aimed to determine if galactose-deficient IgA1 is related to glucose metabolism. METHODS: IgA nephropathy was identified from the renal biopsies of 108 adult patients enrolled in our study with 60 healthy controls. The concentration of serum lactose, galactose, and lactase was measured. The relationship between glucose metabolism, proteinuria, and renal pathological changes was studied. RESULTS: The circulating lactose level was higher in IgAN patients compared to that in the healthy controls [143.9 (93.9-225.6) vs. 77.9 (54.9 - 209.6); p < 0.001]. The circulating lactase level was lower in IgAN patients than that in the healthy controls (229.9 ± 57.56 vs. 270.0 ± 69.30; p < 0.001). Serum galactose level of IgAN patients was lower than that of healthy controls but without significant differences. Lactose levels showed a significant positive correlation with 24-h proteinuria (r = 0.222; p = 0.021). CONCLUSION: The differences in lactose and lactase from the IgAN patients and healthy controls may be an indicator of the possible pathogenesis of IgAN. The level of serum lactose was correlated with the level of 24-h urinary protein during the same period, suggesting that it plays a role in IgA kidney disease progression. Future studies are required to validate our findings during the follow-up and investigate the underlying mechanisms.
Assuntos
Glicemia/metabolismo , Galactose/sangue , Glomerulonefrite por IGA , Imunoglobulina A/sangue , Lactase/sangue , Proteinúria , Adulto , Feminino , Glomerulonefrite por IGA/sangue , Glomerulonefrite por IGA/diagnóstico , Glomerulonefrite por IGA/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Proteinúria/sangue , Proteinúria/diagnóstico , Proteinúria/patologiaRESUMO
A thorough understanding of epigenetics regulatory mechanisms of premature ovarian failure (POF) is still lacking. Here, we found that cyclophosphamide induced significantly decrease in α-Klotho (Kl) expression in mouse ovarian granulosa cells (mOGCs), suggesting that cyclophosphamide inhibited Kl expression. Cyclophosphamide also significantly accelerated ageing and led to a decline in the pregnancy rate of C. elegans. We subsequently noted that the pathological condition exhibited by Kl-/- mice was similar to that observed in cyclophosphamide-induced POF mice. Furthermore, the mOGCs in both types of mice showed significant signs of oxidative stress damage, including decreased SOD and ATP, increased ROS levels. Detailed analyses revealed that the decreased Kl expression led to the reduced expression of autophagy-related proteins in mOGCs, which resulted in decreased autophagy activity. Finally, we found that cyclophosphamide attenuated the autophagy function of mOGCs via upregulating microRNA-15b expression, which silenced the endogenous Kl mRNA expression and stimulated the activity of the downstream TGFß1/Smad pathway. Therefore, we demonstrated that Kl was one of the key inhibitory factors in the development of POF. It elucidated the underlying epigenetic regulatory mechanism, whereby cyclophosphamide-dependent microRNA-15b inhibited Kl expression, leading to the reduced ability of mOGCs to induce autophagy and ROS scavenging, ultimately causing POF.
Assuntos
Glucuronidase/genética , Células da Granulosa/metabolismo , MicroRNAs/genética , Insuficiência Ovariana Primária/genética , Animais , Autofagia/efeitos dos fármacos , Ciclofosfamida/farmacologia , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Células da Granulosa/patologia , Humanos , Proteínas Klotho , Camundongos , Folículo Ovariano/metabolismo , Folículo Ovariano/patologia , Gravidez , Insuficiência Ovariana Primária/tratamento farmacológico , Insuficiência Ovariana Primária/patologia , Transdução de Sinais/efeitos dos fármacos , Proteínas Smad/genética , Fator de Crescimento Transformador beta1/genéticaRESUMO
To determine whether -344T/C CYP11B2 promoter polymorphism affects serum aldosterone levels and whether this polymorphism is an indicator of eGFR decline in patients with chronic kidney disease. -344 C/T CYP11B2 gene polymorphism analysis was performed in 96 adults with stages 1-5 CKD by using polymerase chain reaction. Serum aldosterone levels were measured at baseline and at 1.5-year follow-up. The primary outcome was the annual eGFR decline and the secondary outcome was the occurrence of cardio-cerebrovascular events. The genotype distribution of -344T/C SNP in the patients with CKD was: CC (9.4%), CT (53.1%), and TT (37.5%), nearly similar to the healthy non-CKD individuals as reported. Mean aldosterone levels were highest in the TT group and lowest in CC group (p = 0.036). Serum aldosterone level also showed a negative correlation with baseline eGFR in patients with eGFR >60 mL/min (r = -0.403, p < 0.001). The mean annual eGFR decline ratio was highest in the TT group and lowest in the CC group (p = 0.011). The incidence of cardio-cerebrovascular accidents was significantly higher in the TT group than in the CC and CT groups (p = 0.033). -344T/C promoter polymorphism of CYP11B2 modulated aldosterone levels in patients with all stages of CKD and was predictive of annual eGFR decline in CKD stages 3-4. In addition, the -344 T allele appeared to be an independent predictor of cardio-cerebrovascular events.
Assuntos
Aldosterona/metabolismo , Citocromo P-450 CYP11B2/genética , Taxa de Filtração Glomerular , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas , Insuficiência Renal Crônica , Adulto , Idoso , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/fisiopatologia , Transtornos Cerebrovasculares/etiologia , Transtornos Cerebrovasculares/genética , Transtornos Cerebrovasculares/fisiopatologia , Citocromo P-450 CYP11B2/metabolismo , Progressão da Doença , Regulação para Baixo , Feminino , Seguimentos , Taxa de Filtração Glomerular/genética , Humanos , Masculino , Pessoa de Meia-Idade , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/patologia , Insuficiência Renal Crônica/fisiopatologiaRESUMO
RATIONALE: Inflammatory demyelinating neuropathies such as Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP), and focal segmental glomerulosclerosis (FSGS) are autoimmune disorders that may have a common pathogenesis. Here, we describe 2 unique cases of FSGS, 1 with GBS and the other with CIPD. We believe that reviewing these multisystemic diseases will help in better understanding of FSGS pathogenesis. PATIENT CONCERNS: The 1st patient, a 66-year-old woman, complained of tingling and numbness in the limbs and within 2 days, she developed progressive muscle weakness. The 2nd patient was a 63-year-old man with a complaint of lower-limb edema, lower-limb weakness, and numbness. DIAGNOSIS: In the 1st patient, a diagnosis of GBS was confirmed with the nerve conduction velocity test as well as CSF studies. A renal biopsy revealed FSGS. The 2nd patient was diagnosed with CIDP and a subsequent renal biopsy revealed FSGS. INTERVENTIONS: Large dose of steroid with calcineurin inhibitor, intravenous immunoglobulin, and supportive treatment. OUTCOMES: Neurologic symptoms disappeared, urine protein was maintained at low levels, and no further recurrences were noted in 2 cases. INF2 gene mutation was not found in either case. LESSONS: Co-occurrence of inflammatory demyelinating polyneuropathy, GBS, CIDP, and FSGS suggests synergistic cellular and humoral autoimmune mechanisms related to either cross-reactivity within antigenic targets or mimicry epitopes. Further follow-up and intensive study for the pathogenesis are necessary.