RESUMEN
Mitochondrial dysfunction is a pivotal event contributing to the development of ageing-related kidney disorders. Lon protease 1 (LONP1) has been reported to be responsible for ageing-related renal fibrosis; however, the underlying mechanism(s) of LONP1-driven kidney ageing with respect to mitochondrial disturbances remains to be further explored. The level of LONP1 was tested in the kidneys of aged humans and mice. Renal fibrosis and mitochondrial quality control were confirmed in the kidneys of aged mice. Effects of LONP1 silencing or overexpression on renal fibrosis and mitochondrial quality control were explored. In addition, N6-methyladenosine (m6A) modification and methyltransferase like 3 (METTL3) levels, the relationship between LONP1 and METTL3, and the impacts of METTL3 overexpression on mitochondrial functions were confirmed. Furthermore, the expression of insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2) and the regulatory effects of IGF2BP2 on LONP1 were confirmed in vitro. LONP1 expression was reduced in the kidneys of aged humans and mice, accompanied by renal fibrosis and mitochondrial dysregulation. Overexpression of LONP1 alleviated renal fibrosis and maintained mitochondrial homeostasis, while silencing of LONP1 had the opposite effect. Impaired METTL3-m6A signalling contributed at least in part to ageing-induced LONP1 modification, reducing subsequent degradation in an IGF2BP2-dependent manner. Moreover, METTL3 overexpression alleviated proximal tubule cell injury, preserved mitochondrial stability, inhibited LONP1 degradation, and protected mitochondrial functions. LONP1 mediates mitochondrial function in kidney ageing and that targeting LONP1 may be a potential therapeutic strategy for improving ageing-related renal fibrosis.
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Adenosina , Envejecimiento , Fibrosis , Homeostasis , Enfermedades Renales , Riñón , Metiltransferasas , Mitocondrias , Proteínas Mitocondriales , Proteínas de Unión al ARN , Mitocondrias/metabolismo , Animales , Metiltransferasas/metabolismo , Metiltransferasas/genética , Humanos , Envejecimiento/metabolismo , Ratones , Proteínas Mitocondriales/metabolismo , Proteínas Mitocondriales/genética , Riñón/patología , Riñón/metabolismo , Masculino , Proteínas de Unión al ARN/metabolismo , Proteínas de Unión al ARN/genética , Adenosina/análogos & derivados , Adenosina/metabolismo , Enfermedades Renales/metabolismo , Enfermedades Renales/patología , Enfermedades Renales/etiología , Enfermedades Renales/genética , Proteasas ATP-Dependientes/metabolismo , Proteasas ATP-Dependientes/genética , Transducción de Señal , Ratones Endogámicos C57BLRESUMEN
BACKGROUNDIt is unknown whether the risk of kidney disease progression and failure differs between patients with and without genetic kidney disorders.METHODSThree cohorts were evaluated: the prospective Cure Glomerulonephropathy Network (CureGN) and 2 retrospective cohorts from Columbia University, including 5,727 adults and children with kidney disease from any etiology who underwent whole-genome or exome sequencing. The effects of monogenic kidney disorders and APOL1 kidney-risk genotypes on the risk of kidney failure, estimated glomerular filtration rate (eGFR) decline, and disease remission rates were evaluated along with diagnostic yields and the impact of American College of Medical Genetics secondary findings (ACMG SFs).RESULTSMonogenic kidney disorders were identified in 371 patients (6.5%), high-risk APOL1 genotypes in 318 (5.5%), and ACMG SFs in 100 (5.2%). Family history of kidney disease was the strongest predictor of monogenic disorders. After adjustment for traditional risk factors, monogenic kidney disorders were associated with an increased risk of kidney failure (hazard ratio [HR] = 1.72), higher rate of eGFR decline (-3.06 vs. 0.25 mL/min/1.73 m2/year), and lower risk of complete remission (odds ratioNot achieving CR = 5.25). High-risk APOL1 genotypes were associated with an increased risk of kidney failure (HR = 1.67) and faster eGFR decline (-2.28 vs. 0.25 mL/min/1.73 m2), replicating prior findings. ACMG SFs were not associated with personal or family history of associated diseases, but were predicted to impact care in 70% of cases.CONCLUSIONSMonogenic kidney disorders were associated with an increased risk of kidney failure, faster eGFR decline, and lower rates of complete remission, suggesting opportunities for early identification and intervention based on molecular diagnosis.TRIAL REGISTRATIONNA.FUNDINGNational Institute of Diabetes and Digestive and Kidney Diseases grants U24DK100845 (formerly UM1DK100845), U01DK100846 (formerly UM1DK100846), U01DK100876 (formerly UM1DK100876), U01DK100866 (formerly UM1DK100866), U01DK100867 (formerly UM1DK100867), U24DK100845, DK081943, RC2DK116690, 2U01DK100876, 1R01DK136765, 5R01DK082753, and RC2-DK122397; NephCure Kidney International; Department of Defense Research Awards PR201425, W81XWH-16-1-0451, and W81XWH-22-1-0966; National Center for Advancing Translational Sciences grant UL1TR001873; National Library of Medicine grant R01LM013061; National Human Genome Research Institute grant 2U01HG008680.
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Apolipoproteína L1 , Tasa de Filtración Glomerular , Insuficiencia Renal , Humanos , Masculino , Femenino , Adulto , Apolipoproteína L1/genética , Persona de Mediana Edad , Insuficiencia Renal/genética , Factores de Riesgo , Niño , Estudios Retrospectivos , Adolescente , Estudios Prospectivos , Enfermedades Renales/genéticaRESUMEN
Peroxisome proliferator-activated receptor-alpha (PPAR-α) and its exogenous activators (fibrates) promote autophagy. However, whether the deleterious effects of PPAR-α deficiency on doxorubicin (DOX)-induced podocytopathy are associated with reduced autophagy remains to be clarified. We investigated the mechanisms of PPAR-α in DOX-induced podocytopathy and tubular injury in PPAR-α knockout (PAKO) mice and in a murine podocyte cell line. DOX-treated PAKO mice showed higher serum levels of triglycerides and non-esterified fatty acids and more severe podocytopathy than DOX-treated wild-type mice, as evidenced by higher urinary levels of proteins and podocalyxin at 3 days to 2 weeks and higher blood urea nitrogen and serum creatinine levels at 4 weeks. Additionally, there was an increased accumulation of p62, a negative autophagy marker, in the glomerular and tubular regions in DOX-treated PAKO mice at Day 9. Moreover, DOX-treated PAKO mice showed more severe glomerulosclerosis and tubular damage and lower podocalyxin expression in the kidneys than DOX-treated control mice at 4 weeks. Furthermore, DOX treatment increased p-p53, an apoptosis marker, and cleaved the caspase-3 levels and induced apoptosis, which was ameliorated by fenofibrate, a PPAR-α activator. Fenofibrate further enhanced AMPK activation and autophagy under fed and fasting conditions. Conclusively, PPAR-α deficiency enhances DOX-induced podocytopathy, glomerulosclerosis, and tubular injury, possibly by reducing autophagic activity in mouse kidneys.
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Autofagia , Doxorrubicina , Ratones Noqueados , PPAR alfa , Podocitos , Animales , Podocitos/metabolismo , Podocitos/patología , Podocitos/efectos de los fármacos , Doxorrubicina/efectos adversos , PPAR alfa/metabolismo , PPAR alfa/genética , Ratones , Autofagia/efectos de los fármacos , Línea Celular , Enfermedades Renales/inducido químicamente , Enfermedades Renales/patología , Enfermedades Renales/metabolismo , Enfermedades Renales/genética , Apoptosis/efectos de los fármacos , Fenofibrato/farmacología , MasculinoRESUMEN
INTRODUCTION: Angiogenesis is closely related to renal fibrosis; however, its basic mechanism remains unclear. In our study, we found that nuclear receptor 4A1 (NR4A1) inhibits vascular endothelial growth factor A (VEGFA)-induced angiogenesis, ameliorating renal fibrosis. METHODS: We prepared a renal fibrosis animal model with unilateral ureteral obstruction (UUO) and NR4A1 knockdown UUO mice model, Using Human umbilical vein endothelial cells (HUVECs) to conduct all in vitro experiments. We then detected and analyzed the expression levels of NR4A1 and other genes related to angiogenesis and fibrosis. RESULTS: The angiogenesis related genes, such as VEGFA, vascular endothelial growth factor receptor-2 (VEGFR-2), endoglin (CD105), as well as the expression of fibrosis related genes that included, α-smooth muscle actin (α-SMA), Vimentin, and Collagen I are all significantly increased in the UUO rat model. In addition, the expression of NR4A1 of the kidney tissue of UUO rats was significantly reduced. Therefore, according to the above results, we speculated that angiogenesis may exacerbate renal fibrosis and NR4A1 may repress renal fibrosis by inhibiting angiogenesis. To further verify the above results, we used VEGFA to stimulate HUVECs with (or without) overexpression or knockdown of NR4A1. The results showed that with prolonged stimulation using VEGFA, the expression of NR4A1 decreases. Overexpression of NR4A1 significantly inhibits the expression of related indicators of angiogenesis and renal fibrosis. Furthermore, knockdown of NR4A1 induces endothelial cell proliferation and migration; therefore, exacerbating angiogenesis and fibrosis. Finally, the results of NR4A1 knockdown UUO mice showed that knockdown of NR4A1 can aggravating kidney damage and induce the expression of angiogenesis and renal fibrosis related indicators, while UUO can significantly induce kidney damage, angiogenesis and renal fibrosis. When knockdown of NR4A1, renal kidney damage, angiogenesis and fibrosis becomes more severe than UUO. Thus, all of these results indicate that NR4A1 can ameliorate renal fibrosis by inhibiting angiogenesis. CONCLUSIONS: NR4A1 can inhibit angiogenesis to ameliorate renal fibrosis.
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Fibrosis , Células Endoteliales de la Vena Umbilical Humana , Enfermedades Renales , Riñón , Neovascularización Patológica , Miembro 1 del Grupo A de la Subfamilia 4 de Receptores Nucleares , Obstrucción Ureteral , Factor A de Crecimiento Endotelial Vascular , Animales , Humanos , Miembro 1 del Grupo A de la Subfamilia 4 de Receptores Nucleares/genética , Miembro 1 del Grupo A de la Subfamilia 4 de Receptores Nucleares/metabolismo , Ratas , Factor A de Crecimiento Endotelial Vascular/metabolismo , Factor A de Crecimiento Endotelial Vascular/genética , Obstrucción Ureteral/patología , Obstrucción Ureteral/metabolismo , Obstrucción Ureteral/genética , Obstrucción Ureteral/complicaciones , Neovascularización Patológica/genética , Neovascularización Patológica/metabolismo , Neovascularización Patológica/patología , Riñón/patología , Riñón/metabolismo , Riñón/irrigación sanguínea , Enfermedades Renales/metabolismo , Enfermedades Renales/patología , Enfermedades Renales/genética , Masculino , Modelos Animales de Enfermedad , Ratones , Ratas Sprague-Dawley , Proliferación Celular , AngiogénesisRESUMEN
WT1 encodes a podocyte transcription factor whose variants can cause an untreatable glomerular disease in early childhood. Although WT1 regulates many podocyte genes, it is poorly understood which of them are initiators in disease and how they subsequently influence other cell-types in the glomerulus. We hypothesised that this could be resolved using single-cell RNA sequencing (scRNA-seq) and ligand-receptor analysis to profile glomerular cell-cell communication during the early stages of disease in mice harbouring an orthologous human mutation in WT1 (Wt1R394W/+). Podocytes were the most dysregulated cell-type in the early stages of Wt1R394W/+ disease, with disrupted angiogenic signalling between podocytes and the endothelium, including the significant downregulation of transcripts for the vascular factors Vegfa and Nrp1. These signalling changes preceded glomerular endothelial cell loss in advancing disease, a feature also observed in biopsy samples from human WT1 glomerulopathies. Addition of conditioned medium from murine Wt1R394W/+ primary podocytes to wild-type glomerular endothelial cells resulted in impaired endothelial looping and reduced vascular complexity. Despite the loss of key angiogenic molecules in Wt1R394W/+ podocytes, the pro-vascular molecule adrenomedullin was upregulated in Wt1R394W/+ podocytes and plasma and its further administration was able to rescue the impaired looping observed when glomerular endothelium was exposed to Wt1R394W/+ podocyte medium. In comparative analyses, adrenomedullin upregulation was part of a common injury signature across multiple murine and human glomerular disease datasets, whilst other gene changes were unique to WT1 disease. Collectively, our study describes a novel role for altered angiogenic signalling in the initiation of WT1 glomerulopathy. We also identify adrenomedullin as a proangiogenic factor, which despite being upregulated in early injury, offers an insufficient protective response due to the wider milieu of dampened vascular signalling that results in endothelial cell loss in later disease. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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Glomérulos Renales , Podocitos , Transducción de Señal , Análisis de la Célula Individual , Transcriptoma , Proteínas WT1 , Animales , Podocitos/metabolismo , Podocitos/patología , Proteínas WT1/metabolismo , Proteínas WT1/genética , Humanos , Glomérulos Renales/metabolismo , Glomérulos Renales/patología , Glomérulos Renales/irrigación sanguínea , Células Endoteliales/metabolismo , Células Endoteliales/patología , Ratones , Neovascularización Patológica/genética , Neovascularización Patológica/metabolismo , Modelos Animales de Enfermedad , Mutación , Enfermedades Renales/genética , Enfermedades Renales/metabolismo , Enfermedades Renales/patología , Adrenomedulina/genética , Adrenomedulina/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Factor A de Crecimiento Endotelial Vascular/genética , Comunicación Celular , Células CultivadasRESUMEN
OBJECTIVE: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) target the reabsorption of sodium and glucose in the kidney proximal tubules to reduce blood sugar levels. However, clinical randomized controlled trials on SGLT2i have yielded inconsistent results, necessitating further research into their efficacy and safety for specific cardiac and renal diseases. METHODS: "Sodium in urine" was selected as a downstream biomarker of SGLT2i. Single nucleotide polymorphisms were extracted from genome-wide association study data as instrumental variables. Mendelian randomization analysis was then conducted for cardiac and renal diseases and potential adverse events. The causal effects of SGLT2i on these diseases were determined based on inverse variance weighted results, followed by sensitivity and pleiotropy tests. RESULTS: SGLT2i had a significant protective effect against nephrotic syndrome (odds ratio [OR] 0.0011, 95% confidence interval [CI] 0.000-0.237), chronic glomerulonephritis (OR 0.0002, 95% CI 0.000-0.21), and hypertensive nephropathy (OR 0.0003, 95% CI 0.000-0.785). No causal effects were observed between SGLT2i and cardiac diseases or potential adverse events. CONCLUSIONS: SGLT2i can act as protective factors against nephrotic syndrome, chronic glomerulonephritis, and hypertensive nephropathy.
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Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Polimorfismo de Nucleótido Simple , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Humanos , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Inhibidores del Cotransportador de Sodio-Glucosa 2/efectos adversos , Síndrome Nefrótico/genética , Síndrome Nefrótico/tratamiento farmacológico , Enfermedades Renales/genética , Sodio/orina , Sodio/sangre , Glomerulonefritis/genética , Glomerulonefritis/tratamiento farmacológico , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Cardiopatías/genéticaRESUMEN
The KidGen Collaborative's Policy Implementation Workshop 2023 celebrated the 10th anniversary of Australia's first kidney genetics clinic in Brisbane. This event marked the establishment of a national network now comprising 19 kidney genetics clinics across Australia, all dedicated to providing equitable access to genomic testing for families affected by genetic kidney diseases. The workshop reflected on past progress and outlined future objectives for kidney genetics in Australia, recognising the collaborative efforts of clinical teams, researchers, and patients. Key insights from the workshop are documented in the proceedings.
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Enfermedades Renales , Humanos , Australia , Enfermedades Renales/genética , Pruebas Genéticas/tendenciasRESUMEN
MicroRNAs (miRNAs) are small, non-coding RNA molecules that play a crucial role in regulating gene expression by inhibiting the translation of their specific target messenger RNAs. To date, numerous studies have demonstrated changes in the expression of miRNAs in the kidneys throughout the progression of both acute kidney injury (AKI) and chronic kidney disease (CKD) in both human patients and experimental models. The role of specific microRNAs in the pathogenesis of kidney diseases has also been demonstrated. Further studies have elucidated the regulation of these microRNAs in diseased kidneys. Besides, certain miRNAs are detected in plasma and/or urine in kidney diseases and are potential diagnostic biomarkers. In this review, we provide an overview of recent developments in our understanding of how miRNAs contribute to kidney diseases. We also explore the potential of miRNAs as both biomarkers and therapeutic targets for these conditions, and highlight future research directions.
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Biomarcadores , Enfermedades Renales , MicroARNs , Humanos , MicroARNs/genética , Biomarcadores/metabolismo , Animales , Enfermedades Renales/genética , Enfermedades Renales/metabolismo , Lesión Renal Aguda/metabolismo , Lesión Renal Aguda/genética , Insuficiencia Renal Crónica/genética , Insuficiencia Renal Crónica/metabolismo , Regulación de la Expresión GénicaRESUMEN
Macrophage alternative activation is involved in kidney fibrosis. Previous researches have documented that the transcriptional regulators Yes-associated protein (Yap)/transcriptional coactivator with PDZ-binding motif (Taz) are linked to organ fibrosis. However, limited knowledge exists regarding the function and mechanisms of their downstream molecules in regulating macrophage activation and kidney fibrosis. In this paper, we observed that the Hippo pathway was suppressed in macrophages derived from fibrotic kidneys in mice. Knockout of Taz or Tead1 in macrophages inhibited the alternative activation of macrophages and reduced kidney fibrosis. Additionally, by using bone marrow-derived macrophages (BMDMs), we investigated that knockout of Taz or Tead1 in macrophages impeded both cell proliferation and migration. Moreover, deletion of Tead1 reduces p-Smad3 and Smad3 abundance in macrophages. And chromatin immunoprecipitation (ChIP) assays showed that Tead1 could directly bind to the promoter region of Smad3. Collectively, these results indicate that Tead1 knockout in macrophages could reduce TGFß1-induced phosphorylation Smad3 via transcriptional downregulation of Smad3, thus suppressing macrophage alternative activation and IRI-induced kidney fibrosis.
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Proteínas de Unión al ADN , Fibrosis , Activación de Macrófagos , Macrófagos , Ratones Noqueados , Proteína smad3 , Factores de Transcripción de Dominio TEA , Factores de Transcripción , Animales , Masculino , Ratones , Aciltransferasas , Proliferación Celular , Modelos Animales de Enfermedad , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Vía de Señalización Hippo , Riñón/patología , Riñón/metabolismo , Enfermedades Renales/genética , Enfermedades Renales/patología , Enfermedades Renales/metabolismo , Enfermedades Renales/inmunología , Activación de Macrófagos/genética , Activación de Macrófagos/inmunología , Macrófagos/inmunología , Macrófagos/metabolismo , Ratones Endogámicos C57BL , Fosforilación , Transducción de Señal , Proteína smad3/metabolismo , Proteína smad3/genética , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Factor de Crecimiento Transformador beta1/metabolismo , Regulación hacia ArribaRESUMEN
We determined the epigenetic mechanisms regulating mean arterial pressure (MAP) and renal dysfunction in guanylyl cyclase/natriuretic peptide receptor-A (GC-A/NPRA) gene-targeted mice. The Npr1 (encoding NPRA) gene-targeted mice were treated with class 1 specific histone deacetylase inhibitor (HDACi) mocetinostat (MGCD) to determine the epigenetic changes in a sex-specific manner. Adult male and female Npr1 haplotype (1-copy; Npr1+/-), wild-type (2-copy; Npr1+/+), and gene-duplicated heterozygous (3-copy; Npr1++/+) mice were intraperitoneally injected with MGCD (2 mg/kg) for 14 days. BP, renal function, histopathology, and epigenetic changes were measured. One-copy male mice showed significantly increased MAP, renal dysfunction, and fibrosis than 2-copy and 3-copy mice. Furthermore, HDAC1/2, collagen1alpha-2 (Col1α-2), and alpha smooth muscle actin (α-SMA) were significantly increased in 1-copy mice compared with 2-copy controls. The expression of antifibrotic microRNA-133a was attenuated in 1-copy mice but to a greater extent in males than females. NF-κB was localized at significantly lower levels in cytoplasm than in the nucleus with stronger DNA binding activity in 1-copy mice. MGCD significantly lowered BP, improved creatinine clearance, and repaired renal histopathology. The inhibition of class I HDACs led to a sex-dependent distinctive stimulation of acetylated positive histone marks and inhibition of methylated repressive histone marks in Npr1 1-copy mice; however, it epigenetically lowered MAP, repaired renal fibrosis, and proteinuria and suppressed NF-kB differentially in males versus females. Our results suggest a role for epigenetic targets affecting hypertension and renal dysfunction in a sex-specific manner.
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Presión Sanguínea , Epigénesis Genética , Receptores del Factor Natriurético Atrial , Animales , Femenino , Masculino , Receptores del Factor Natriurético Atrial/genética , Receptores del Factor Natriurético Atrial/metabolismo , Ratones , Presión Sanguínea/efectos de los fármacos , Riñón/metabolismo , Riñón/patología , Inhibidores de Histona Desacetilasas/farmacología , Enfermedades Renales/genética , Enfermedades Renales/metabolismo , Enfermedades Renales/patologíaRESUMEN
MicroRNAs (miRNAs) are 18-25 nucleotides long, single-stranded, non-coding RNA molecules that regulate gene expression. They play a crucial role in maintaining normal cellular functions and homeostasis in organisms. Studies have shown that miR-124-3p is highly expressed in brain tissue and plays a significant role in nervous system development. It is also described as a tumor suppressor, regulating biological processes like cancer cell proliferation, apoptosis, migration, and invasion by controlling multiple downstream target genes. miR-124-3p has been found to be involved in the progression of various kidney diseases, including diabetic kidney disease, calcium oxalate kidney stones, acute kidney injury, lupus nephritis, and renal interstitial fibrosis. It mediates these processes through mechanisms like oxidative stress, inflammation, autophagy, and ferroptosis. To lay the foundation for future therapeutic strategies, this research group reviewed recent studies on the functional roles of miR-124-3p in renal diseases and the regulation of its downstream target genes. Additionally, the feasibility, limitations, and potential application of miR-124-3p as a diagnostic biomarker and therapeutic target were thoroughly investigated.
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Enfermedades Renales , MicroARNs , MicroARNs/metabolismo , MicroARNs/genética , Humanos , Enfermedades Renales/genética , Enfermedades Renales/metabolismo , Nefropatías Diabéticas/metabolismo , Nefropatías Diabéticas/genética , Lesión Renal Aguda/genética , Lesión Renal Aguda/metabolismo , Animales , Estrés Oxidativo , Nefritis Lúpica/genética , Nefritis Lúpica/metabolismo , Cálculos Renales/genética , Cálculos Renales/metabolismoRESUMEN
Renal fibrosis is among the major factors contributing to the development of chronic kidney disease. In this regard, although N6-methyladenosine (m6A) modification and micro-RNAs (miRNAs) have been established to play key roles in diverse physiological processes and disease/disorder development, further research is required to identify the probable mechanisms and processes associated with their involvement in renal fibrosis. In this study, we show that transforming growth factor ß1 (TGF-ß1)-induced human proximal tubule epithelial cells (HK2) are characterized by dose-dependently higher methyltransferase-like 3 (METTL3) expression. Furthermore, METTL3 was found to enhance pri-miR-199a-3p maturation and miR-199a-3p expression in an m6A-dependent manner, whereas miR-199a-3p sponges prostate apoptotic response 4 (Par4), thereby regulating its expression. Collectively, our findings in this study indicate that the METTL3/miR-199a-3p/Par4 axis plays a key role in the development of obstructive nephrogenic fibrosis.
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Fibrosis , Metiltransferasas , MicroARNs , Factor de Crecimiento Transformador beta1 , Metiltransferasas/genética , Metiltransferasas/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Humanos , Línea Celular , Factor de Crecimiento Transformador beta1/metabolismo , Factor de Crecimiento Transformador beta1/genética , Enfermedades Renales/genética , Enfermedades Renales/patología , Enfermedades Renales/metabolismo , Túbulos Renales Proximales/patología , Túbulos Renales Proximales/metabolismo , Animales , Regulación de la Expresión Génica , Transducción de Señal/genética , Adenosina/análogos & derivados , Adenosina/metabolismoRESUMEN
OBJECTIVE: This study aimed to explore the potential role of CYP3A5 (c. 6986A>G) gene polymorphism in predicting kidney function impairment in patients with hypertension who did not have elevated serum cystatin C. METHODS: We recruited a group of patients with hypertension who did not have elevated cystatin C and analyzed the CYP3A5 (c. 6986A>G) gene polymorphism. Chi-square tests were used to compare the clinical characteristics and genotypic distribution between the two groups. Logistic regression analysis was used to explore the association between CYP3A5 (c.6986A>G) gene polymorphism and renal function impairment in hypertension with non-elevated cystatin. RESULTS: In patients with hypertension who participated in the study, there was a significant association between CYP3A5 (c. 6986A>G) gene polymorphism and kidney function impairment (p < 0.05). Patients with the CYP3A5 (c. 6986A>G) mutation display a greater risk of kidney function impairment. CONCLUSION: CYP3A5 (c. 6986A>G) gene AA homozygote polymorphism significantly increases risk of kidney function impairment in patients with hypertension with normal cystatin C. However, further studies are needed to validate this association and to further understand the mechanism of CYP3A5 (c. 6986A>G) gene polymorphism in kidney function impairment in patients with hypertension.
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Biomarcadores , Cistatina C , Citocromo P-450 CYP3A , Predisposición Genética a la Enfermedad , Hipertensión , Riñón , Polimorfismo de Nucleótido Simple , Humanos , Citocromo P-450 CYP3A/genética , Masculino , Femenino , Persona de Mediana Edad , Hipertensión/genética , Hipertensión/fisiopatología , Hipertensión/diagnóstico , Cistatina C/sangre , Cistatina C/genética , Biomarcadores/sangre , Factores de Riesgo , Riñón/fisiopatología , Fenotipo , Estudios de Asociación Genética , Homocigoto , Adulto , Anciano , Enfermedades Renales/genética , Enfermedades Renales/diagnóstico , Enfermedades Renales/sangre , Enfermedades Renales/fisiopatología , Enfermedades Renales/enzimología , Frecuencia de los Genes , Estudios de Casos y Controles , Medición de RiesgoRESUMEN
OBJECTIVE: The purpose of this study was to investigate the role and possible mechanism of lncRNA XIST in renal fibrosis and to provide potential endogenous targets for renal fibrosis in obstructive nephropathy (ON). METHODS: The study included 50 cases of ON with renal fibrosis (samples taken from patients undergoing nephrectomy due to ON) and 50 cases of normal renal tissue (samples taken from patients undergoing total or partial nephrectomy due to accidental injury, congenital malformations, and benign tumors). Treatment of human proximal renal tubular epithelium (HK-2) cells with TGF-ß1 simulated renal fibrosis in vitro. Cell viability and proliferation were measured by CCK-8 and EdU, and cell migration was measured by transwell. XIST, miR-124-3p, ITGB1, and epithelial-mesenchymal transition (EMT)-related proteins (E-cadherin, α-SMA, and fibronectin) were detected by PCR and immunoblot. The targeting relationship between miR-124-3p and XIST or ITGB1 was verified by starBase and dual luciferase reporter gene experiments. In addition, The left ureter was ligated in mice as a model of unilateral ureteral obstruction (UUO), and the renal histopathology was observed by HE staining and Masson staining. RESULTS: ON patients with renal fibrosis had elevated XIST and ITGB1 levels and reduced miR-124-3p levels. The administration of TGF-ß1 exhibited a dose-dependent promotion of HK-2 cell viability, proliferation, migration, and EMT. Conversely, depleting XIST or enhancing miR-124-3p hindered HK-2 cell viability, proliferation, migration, and EMT in TGF-ß1-damaged HK-2 cells HK-2 cells. XIST functioned as a miR-124-3p sponge. Additionally, miR-124-3p negatively regulated ITGB1 expression. Elevating ITGB1 weakened the impact of XIST depletion on TGF-ß1-damaged HK-2 cells. Down-regulating XIST improved renal fibrosis in UUO mice. CONCLUSION: XIST promotes renal fibrosis in ON by elevating miR-124-3p and reducing ITGB1 expressions.
Asunto(s)
Transición Epitelial-Mesenquimal , Fibrosis , Enfermedades Renales , MicroARNs , ARN Largo no Codificante , ARN Largo no Codificante/genética , MicroARNs/genética , MicroARNs/metabolismo , Humanos , Fibrosis/genética , Fibrosis/patología , Fibrosis/metabolismo , Animales , Ratones , Enfermedades Renales/genética , Enfermedades Renales/patología , Enfermedades Renales/metabolismo , Transición Epitelial-Mesenquimal/genética , Integrina beta1/metabolismo , Integrina beta1/genética , Proliferación Celular , Masculino , Movimiento Celular/genética , Riñón/patología , Riñón/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Factor de Crecimiento Transformador beta1/genética , Línea Celular , Femenino , Obstrucción Ureteral/patología , Obstrucción Ureteral/metabolismo , Obstrucción Ureteral/genéticaRESUMEN
Renal fibrosis (RF) is a typical pathological presentation of end-stage chronic kidney disease (CKD) and autosomal dominant polycystic kidney disease (ADPKD). However, the precise regulatory mechanisms governing this re-expression process remain unclear. Differentially expressed microRNAs (miRNAs) associated with RF were screened by microarray analysis using the Gene Expression Omnibus (GEO) database. The miRNAs upstream of the genes in question were predicted using the miRWalk database. The miRNAs involved in the two GEO data sets were intersected to identify key miRNAs; their regulatory pathways were investigated using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Subsequently, the effects and the underlying mechanisms of target miRNA on RF were examined in a unilateral ureteral obstruction (UUO)-induced mice renal fibrotic model and a transforming growth factor-ß1 (TGF-ß1)-induced tubular epithelium (HK-2) fibrotic cell model. In total, 109 and 32 differentially expressed miRNAs were identified in the GSE133530 and GSE80247 data sets, respectively. GREM1 was identified as a hub gene, where its 2196 upstream miRNAs were predicted; miR-574-5p was found to be downregulated and closely related to fibrosis after data set intersection and enrichment analyses, thus was selected for further investigation. A differential expression heatmap (GSE162794) showed that miR-542-5p was downregulated. The expression of GREM1 mRNA was upregulated, whereas that of miR-542-5p was downregulated in UUO mice and fibrotic HK-2 cells as compared with the relevant controls. The binding site of miR-542-5p was predicted at the 3'UTR region of GREM1 and was confirmed by subsequent dual luciferase reporter gene assay. Western blot analysis showed that Gremlin-1 and Fibronectin were significantly upregulated after induction of TGF-ß1; when miR-542-5p was overexpressed or GREM1 mRNA was interfered, the upregulations of Gremlin-1 and Fibronectin were significantly reduced. Our research demonstrates that miR-542-5p plays a critical role in the progression of RF, and thus may be a promising therapeutic target for CKD and ADPKD.
Asunto(s)
Fibrosis , MicroARNs , MicroARNs/genética , MicroARNs/metabolismo , Fibrosis/genética , Animales , Ratones , Humanos , Masculino , Péptidos y Proteínas de Señalización Intercelular/genética , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Línea Celular , Ratones Endogámicos C57BL , Riñón/patología , Riñón/metabolismo , Progresión de la Enfermedad , Obstrucción Ureteral/genética , Obstrucción Ureteral/patología , Factor de Crecimiento Transformador beta1/genética , Factor de Crecimiento Transformador beta1/metabolismo , Enfermedades Renales/genética , Enfermedades Renales/patología , Enfermedades Renales/metabolismoRESUMEN
Celiac disease, characterized as an autoimmune disorder, possesses the capacity to affect multiple organs and systems. Earlier research has indicated an increased risk of kidney diseases associated with celiac disease. However, the potential causal relationship between genetic susceptibility to celiac disease and the risk of kidney diseases remains uncertain. We conducted Mendelian randomization analysis using nonoverlapping European population data, examining the link between celiac disease and 10 kidney traits in whole-genome association studies. We employed the inverse variance-weighted method to enhance statistical robustness, and results' reliability was reinforced through rigorous sensitivity analysis. Mendelian randomization analysis revealed a genetic susceptibility of celiac disease to an increased risk of immunoglobulin A nephropathy (OR = 1.44; 95% confidence interval [CI]â =â 1.17-1.78; P = 5.7â ×â 10-4), chronic glomerulonephritis (OR = 1.15; 95% CIâ =â 1.08-1.22; P = 2.58â ×â 10-5), and a decline in estimated glomerular filtration rate (beta = -0.001; P = 2.99â ×â 10-4). Additionally, a potential positive trend in the causal relationship between celiac disease and membranous nephropathy (OR = 1.37; 95% CIâ =â 1.08-1.74; P = 0.01) was observed. Sensitivity analysis indicated the absence of pleiotropy. This study contributes novel evidence establishing a causal link between celiac disease and kidney traits, indicating a potential association between celiac disease and an elevated risk of kidney diseases. The findings provide fresh perspectives for advancing mechanistic and clinical research into kidney diseases associated with celiac disease.
Asunto(s)
Enfermedad Celíaca , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Enfermedad Celíaca/genética , Enfermedad Celíaca/complicaciones , Enfermedad Celíaca/epidemiología , Humanos , Enfermedades Renales/genética , Enfermedades Renales/epidemiología , Enfermedades Renales/etiología , Tasa de Filtración Glomerular , Glomerulonefritis por IGA/genética , Glomerulonefritis por IGA/epidemiología , Causalidad , Glomerulonefritis Membranosa/genética , Glomerulonefritis Membranosa/epidemiologíaRESUMEN
BACKGROUND/AIM: Angiotensinogen (AGT), a precursor of angiotensin II (AngII), contributes to regulating (patho)physiological conditions, including blood pressure changes, inflammation, and kidney fibrosis. However, the precise role of tissue-specific AGT in kidney fibrosis independent of blood pressure remains to be fully understood. This study investigated the source of intrarenal AGT and its role in kidney injury and fibrosis during obstructive nephropathy. MATERIALS AND METHODS: Proximal tubule- (PT, major source secreting AGT in the kidney; PKO) or liver- (major source of circulating AGT; LKO) AGT knockout (KO) mice were subjected to unilateral ureteral obstruction (UUO), a blood pressure-independent fibrosis model. RESULTS: UUO increased AGT mRNA and protein levels in the kidneys. PKO decreased AGT mRNA, but LKO enhanced it in UUO kidneys compared with the control. In contrast, the intrarenal protein levels of AGT increased in PKO, but not in LKO in UUO kidneys, indicating that the liver is a major source of intrarenal AGT protein. Expression of megalin, a PT receptor involved in the uptake of circulating AGT, was down-regulated in UUO kidneys and was independent of PKO or LKO. However, none of these changes prevented UUO-induced tubular injury and kidney fibrosis. CONCLUSION: Hepatic and proximal tubule AGT play distinct roles in contributing to intrarenal AGT levels during UUO, and their genetic inhibitions fail to prevent kidney injury and fibrosis, suggesting a highly complicated signaling pathway of the renin-angiotensin system and an associated compensatory mechanism in obstructive nephropathy.