RESUMEN
Chronic kidney disease (CKD) is associated with various pathologic changes, including elevations in serum phosphate levels (hyperphosphatemia), vascular calcification, and skeletal muscle atrophy. Elevated phosphate can damage vascular smooth muscle cells and cause vascular calcification. Here, we determined whether high phosphate can also affect skeletal muscle cells and whether hyperphosphatemia, in the context of CKD or by itself, is associated with skeletal muscle atrophy. As models of hyperphosphatemia with CKD, we studied mice receiving an adenine-rich diet for 14 weeks and mice with deletion of Collagen 4a3 (Col4a3-/-). As models of hyperphosphatemia without CKD, we analyzed mice receiving a high-phosphate diet for three and six months as well as a genetic model for klotho deficiency (kl/kl). We found that adenine, Col4a3-/-, and kl/kl mice have reduced skeletal muscle mass and function and develop atrophy. Mice on a high-phosphate diet for six months also had lower skeletal muscle mass and function but no significant signs of atrophy, indicating less severe damage compared with the other three models. To determine the potential direct actions of phosphate on skeletal muscle, we cultured primary mouse myotubes in high phosphate concentrations, and we detected the induction of atrophy. We conclude that in experimental mouse models, hyperphosphatemia is sufficient to induce skeletal muscle atrophy and that, among various other factors, elevated phosphate levels might contribute to skeletal muscle injury in CKD.
Asunto(s)
Hiperfosfatemia , Músculo Esquelético , Atrofia Muscular , Fosfatos , Animales , Hiperfosfatemia/patología , Ratones , Atrofia Muscular/patología , Atrofia Muscular/metabolismo , Atrofia Muscular/etiología , Músculo Esquelético/patología , Músculo Esquelético/metabolismo , Fosfatos/sangre , Fosfatos/metabolismo , Insuficiencia Renal Crónica/patología , Insuficiencia Renal Crónica/metabolismo , Modelos Animales de Enfermedad , Ratones Noqueados , Masculino , Colágeno Tipo IV/metabolismo , Colágeno Tipo IV/genética , Ratones Endogámicos C57BL , Proteínas Klotho/metabolismo , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares Esqueléticas/patologíaRESUMEN
Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been shown to be renoprotective in ischemia-reperfusion (I/R) injury, with several proposed mechanisms, though additional mechanisms likely exist. This study investigated the impact of luseogliflozin on kidney fibrosis at 48 h and 1 week post I/R injury in C57BL/6 mice. Luseogliflozin attenuated kidney dysfunction and the acute tubular necrosis score on day 2 post I/R injury, and subsequent fibrosis at 1 week, as determined by Sirius red staining. Metabolomics enrichment analysis of I/R-injured kidneys revealed suppression of the glycolytic system and activation of mitochondrial function under treatment with luseogliflozin. Western blotting showed increased nutrient deprivation signaling with elevated phosphorylated AMP-activated protein kinase and Sirtuin-3 in luseogliflozin-treated kidneys. Luseogliflozin-treated kidneys displayed increased protein levels of carnitine palmitoyl transferase 1α and decreased triglyceride deposition, as determined by oil red O staining, suggesting activated fatty acid oxidation. Luseogliflozin prevented the I/R injury-induced reduction in nuclear factor erythroid 2-related factor 2 activity. Western blotting revealed increased glutathione peroxidase 4 and decreased transferrin receptor protein 1 expression. Immunostaining showed reduced 4-hydroxynonenal and malondialdehyde levels, especially in renal tubules, indicating suppressed ferroptosis. Luseogliflozin may protect the kidney from I/R injury by inhibiting ferroptosis through oxidative stress reduction.
Asunto(s)
Lesión Renal Aguda , Ferroptosis , Ratones Endogámicos C57BL , Insuficiencia Renal Crónica , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Animales , Lesión Renal Aguda/metabolismo , Lesión Renal Aguda/tratamiento farmacológico , Lesión Renal Aguda/patología , Lesión Renal Aguda/prevención & control , Ferroptosis/efectos de los fármacos , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Ratones , Insuficiencia Renal Crónica/tratamiento farmacológico , Insuficiencia Renal Crónica/metabolismo , Insuficiencia Renal Crónica/patología , Masculino , Daño por Reperfusión/metabolismo , Daño por Reperfusión/tratamiento farmacológico , Sorbitol/análogos & derivados , Sorbitol/farmacología , Riñón/metabolismo , Riñón/efectos de los fármacos , Riñón/patología , Estrés Oxidativo/efectos de los fármacos , Fibrosis , Modelos Animales de Enfermedad , Transportador 2 de Sodio-GlucosaRESUMEN
BACKGROUND: The prevalence of vascular calcification (VC) in chronic kidney disease (CKD) patients remains substantial, but currently, there are no effective pharmaceutical therapies available. BRCA1/BRCA2-containing complex subunit 36 (BRCC36) has been implicated in osteoblast osteogenic conversion; however, its specific role in VC remains to be fully elucidated. The aim of this study was to investigate the role and underlying mechanisms of BRCC36 in VC. METHODS: The association between BRCC36 expression and VC was examined in radial arteries from patients with CKD, high-adenine-induced CKD mice, and vascular smooth muscle cells (VSMCs). Western blotting, real-time polymerase chain reaction, immunofluorescence, and immunohistochemistry were used to analyse gene expression. Gain- and loss-of-function experiments were performed to comprehensively investigate the effects of BRCC36 on VC. Coimmunoprecipitation and TOPFlash luciferase assays were utilized to further investigate the regulatory effects of BRCC36 on the Wnt/ß-catenin pathway. RESULTS: BRCC36 expression was downregulated in human calcified radial arteries, calcified aortas from CKD mice, and calcified VSMCs. VSMC-specific BRCC36 overexpression alleviated calcium deposition in the vasculature, whereas BRCC36 depletion aggravated VC progression. Furthermore, BRCC36 inhibited the osteogenic differentiation of VSMCs in vitro. Rescue experiments revealed that BRCC36 exerts the protective effects on VC partly by regulating the Wnt/ß-catenin signalling pathway. Mechanistically, BRCC36 inhibited the Wnt/ß-catenin pathway by decreasing the K63-linked ubiquitination of ß-catenin. Additionally, pioglitazone attenuated VC partly through upregulating BRCC36 expression. CONCLUSIONS: Our research results emphasize the critical role of the BRCC36-ß-catenin axis in VC, suggesting that BRCC36 or ß-catenin may be promising therapeutic targets to prevent the progression of VC in CKD patients.
Asunto(s)
Ratones Endogámicos C57BL , Insuficiencia Renal Crónica , Ubiquitinación , Calcificación Vascular , Vía de Señalización Wnt , beta Catenina , Calcificación Vascular/metabolismo , Calcificación Vascular/patología , Insuficiencia Renal Crónica/metabolismo , Insuficiencia Renal Crónica/patología , Insuficiencia Renal Crónica/complicaciones , Animales , beta Catenina/metabolismo , Humanos , Masculino , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patología , Ratones , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/patología , Osteogénesis , Persona de Mediana Edad , Diferenciación CelularRESUMEN
Renal fibrosis is a long-term and progressively worsening condition that impacts kidney function during aging and in the context of chronic kidney disease (CKD). CKD and renal fibrosis affect approximately 10% of the global population and are prevalent in about half of individuals over the age of 70. Despite ongoing research, the mechanisms underlying renal fibrosis are still not well understood, and there is currently a lack of effective treatments available. In the present study, we demonstrated a significant increase of circPWWP2A in renal tubular cells both in vivo and in vitro models of renal fibrosis. Suppressing circPWWP2A has the potential to reduce mitochondrial dysfunction and the production of mitochondrial reactive oxygen species (mtROS), ultimately leading to the inhibition of renal fibrosis. Whereas, supplementation of circPWWP2A led to more serve mitochondrial dysfunction, mtROS production and renal fibrosis. Mechanistically, we found the expression of circPWWP2A was negatively correlated with the expression of miR-182. And we further confirmed miR-182 was the direct target of circPWWP2A by dual-luciferase reporter assay and RIP assay. Then, we found miR-182 suppressed the expression of ROCK1 in both in vitro and in vivo models of renal fibrosis. Luciferase microRNA target reporter assay further indicated ROCK1 as a direct target of miR-182. Knockdown of ROCK1 inhibits renal fibrosis and mitochondrial dysfunction, suggesting ROCK1 not only served as an injurious role in mitochondrial homeostasis but also a pro-fibrotic factor in CKD. Taking together, our findings suggest that circPWWP2A may promote renal interstitial fibrosis by modulating miR-182/ROCK1-mediated mitochondrial dysfunction.
Asunto(s)
Fibrosis , Riñón , MicroARNs , ARN Circular , Insuficiencia Renal Crónica , Quinasas Asociadas a rho , MicroARNs/metabolismo , MicroARNs/genética , Quinasas Asociadas a rho/metabolismo , Quinasas Asociadas a rho/genética , Animales , ARN Circular/genética , ARN Circular/metabolismo , Ratones , Riñón/patología , Riñón/metabolismo , Masculino , Insuficiencia Renal Crónica/metabolismo , Insuficiencia Renal Crónica/genética , Insuficiencia Renal Crónica/patología , Humanos , Mitocondrias/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Modelos Animales de Enfermedad , Ratones Endogámicos C57BLRESUMEN
Chronic kidney disease (CKD) is characterized by a steady decline in kidney function and affects roughly 10% of the world's population. This review focuses on the critical function of cyclic adenosine monophosphate (cAMP) signaling in CKD, specifically how it influences both protective and pathogenic processes in the kidney. cAMP, a critical secondary messenger, controls a variety of cellular functions, including transcription, metabolism, mitochondrial homeostasis, cell proliferation, and apoptosis. Its compartmentalization inside cellular microdomains ensures accurate signaling. In kidney physiology, cAMP is required for hormone-regulated activities, particularly in the collecting duct, where it promotes water reabsorption through vasopressin signaling. Several illnesses, including Fabry disease, renal cell carcinoma, nephrogenic diabetes insipidus, Bartter syndrome, Liddle syndrome, diabetic nephropathy, autosomal dominant polycystic kidney disease, and renal tubular acidosis, have been linked to dysfunction in the cAMP system. Both cAMP analogs and phosphodiesterase inhibitors have the potential to improve kidney function and reduce kidney damage. Future research should focus on developing targeted PDE inhibitors for the treatment of CKD.
Asunto(s)
AMP Cíclico , Insuficiencia Renal Crónica , Transducción de Señal , Humanos , AMP Cíclico/metabolismo , Insuficiencia Renal Crónica/metabolismo , Insuficiencia Renal Crónica/tratamiento farmacológico , Insuficiencia Renal Crónica/patología , Animales , Transducción de Señal/efectos de los fármacos , Terapia Molecular Dirigida , Riñón/metabolismo , Riñón/patología , Inhibidores de Fosfodiesterasa/uso terapéutico , Inhibidores de Fosfodiesterasa/farmacologíaRESUMEN
Acute kidney injury (AKI) is widely recognized as a precursor to the onset or rapid progression of chronic kidney disease (CKD). However, there is currently no effective treatment available for AKI, underscoring the urgent need for the development of new strategies to improve kidney function. Human placental mesenchymal stromal cells (hpMSCs) were isolated from donor placentas, cultured, and characterized with regard to yield, viability, flow cytometry, and potency. To mimic AKI and its progression to CKD in a rat model, a dedicated sensitive non-clinical bilateral kidney ischemia-reperfusion injury (IRI) model was utilized. The experimental group received 3 × 105 hpMSCs into each kidney, while the control group received IRI and saline and the untreated group received IRI only. Urine, serum, and kidney tissue samples were collected over a period of 28 days. The hpMSCs exhibited consistent yields, viability, and expression of mesenchymal lineage markers, and were also shown to suppress T cell proliferation in a dose-dependent manner. To ensure optimal donor selection, manufacturing optimization, and rigorous quality control, the rigorous Good Manufacturing Practice (GMP) conditions were utilized. The results indicated that hpMSCs increased rat survival rates and improved kidney function by decreasing serum creatinine, urea, potassium, and fractionated potassium levels. Furthermore, the study demonstrated that hpMSCs can prevent the initial stages of kidney structural fibrosis and improve kidney function in the early stages by mitigating late interstitial fibrosis and tubular atrophy. Additionally, a robust manufacturing process with consistent technical parameters was established.
Asunto(s)
Lesión Renal Aguda , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas , Insuficiencia Renal Crónica , Lesión Renal Aguda/terapia , Lesión Renal Aguda/patología , Lesión Renal Aguda/prevención & control , Animales , Insuficiencia Renal Crónica/terapia , Insuficiencia Renal Crónica/patología , Humanos , Ratas , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/metabolismo , Femenino , Embarazo , Trasplante de Células Madre Mesenquimatosas/métodos , Placenta/citología , Daño por Reperfusión/terapia , Daño por Reperfusión/prevención & control , Daño por Reperfusión/patología , Modelos Animales de Enfermedad , Riñón/patología , Ratas Sprague-Dawley , Masculino , Progresión de la EnfermedadRESUMEN
Acute kidney injury (AKI) and chronic kidney disease (CKD) are significant public health issues associated with a long-term increase in mortality risk, resulting from various etiologies including renal ischemia, sepsis, drug toxicity, and diabetes mellitus. Numerous preclinical models have been developed to deepen our understanding of the pathophysiological mechanisms and therapeutic approaches for kidney diseases. Among these, rodent models have proven to be powerful tools in the discovery of novel therapeutics, while the development of kidney organoids has emerged as a promising advancement in the field. This review provides a comprehensive analysis of the construction methodologies, underlying biological mechanisms, and recent therapeutic developments across different AKI and CKD models. Additionally, this review summarizes the advantages, limitations, and challenges inherent in these preclinical models, thereby contributing robust evidence to support the development of effective therapeutic strategies.
Asunto(s)
Modelos Animales de Enfermedad , Animales , Enfermedades Renales/etiología , Enfermedades Renales/patología , Humanos , Lesión Renal Aguda/fisiopatología , Lesión Renal Aguda/patología , Insuficiencia Renal Crónica/patologíaRESUMEN
PURPOSE: This study aimed to investigate the inhibitory effect of chrysophanol on renal fibrosis and its molecular mechanism. METHODS: Initially, potential targets of chrysophanol were predicted through network pharmacology analysis, and a protein-protein interaction network of these targets was constructed using Venn diagrams and the STRING database. GO enrichment analysis predicted the biological process of chrysophanol in treating renal fibrosis. Subsequently, both in vivo and in vitro experiments were conducted using unilateral ureteral obstruction (UUO) induced CKD mouse model and HK-2 cell model, respectively. In the mouse model, different doses of chrysophanol were administered to assess its renal protective effects through biochemical indicators, histological examination, and immunofluorescence staining. In the cell model, the regulatory effect of chrysophanol on the Trx-1/JNK/Cx43 pathway was evaluated using western blotting and flow cytometry. RESULTS: Chrysophanol treatment significantly ameliorated renal dysfunction and histopathological damage in the UUO mouse model, accompanied by a reduction in serum oxidative stress markers. Furthermore, chrysophanol markedly upregulated the expression of Trx-1 in renal tissues and inhibited the activation of the JNK/Cx43 signaling pathway. At the cellular level, chrysophanol enhanced the activity of Trx-1 and downregulated the JNK/Cx43 signaling pathway, thereby inhibiting TGF-ß induced oxidative stress and cell apoptosis. CONCLUSION: This study demonstrated a significant inhibitory effect of chrysophanol on renal fibrosis, mediated by the activation of Trx-1 to inhibit the JNK/Cx43 pathway. These findings provide experimental support for the potential use of chrysophanol as a therapeutic agent for renal fibrosis.
Asunto(s)
Antraquinonas , Modelos Animales de Enfermedad , Fibrosis , Riñón , Obstrucción Ureteral , Animales , Ratones , Fibrosis/tratamiento farmacológico , Masculino , Riñón/patología , Riñón/efectos de los fármacos , Obstrucción Ureteral/complicaciones , Obstrucción Ureteral/tratamiento farmacológico , Antraquinonas/farmacología , Antraquinonas/uso terapéutico , Humanos , Estrés Oxidativo/efectos de los fármacos , Tiorredoxinas/metabolismo , Insuficiencia Renal Crónica/tratamiento farmacológico , Insuficiencia Renal Crónica/metabolismo , Insuficiencia Renal Crónica/patología , Transducción de Señal/efectos de los fármacos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Línea Celular , Ratones Endogámicos C57BL , Apoptosis/efectos de los fármacosRESUMEN
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.
Asunto(s)
Proteínas ADAMTS , Fibrosis , Transducción de Señal , Factor de Crecimiento Transformador beta , Animales , Masculino , Ratones , Proteínas ADAMTS/metabolismo , Riñón/patología , Riñón/metabolismo , Insuficiencia Renal Crónica/metabolismo , Insuficiencia Renal Crónica/patología , Proteínas Smad/metabolismo , Proteína Smad2/metabolismo , Proteína smad3/metabolismo , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
Rationale: Acute kidney injury (AKI) has substantial rates of mortality and morbidity, coupled with an absence of efficacious treatment options. AKI commonly transits into chronic kidney disease (CKD) and ultimately culminates in end-stage renal failure. The interferon-stimulated gene 15 (ISG15) level was upregulated in the kidneys of mice injured by ischemia-reperfusion injury (IRI), cisplatin, or unilateral ureteral obstruction (UUO), however, its role in AKI development and subsequent AKI-to-CKD transition remains unknown. Methods: Isg15 knockout (Isg15 KO) mice challenged with bilateral or unilateral IRI, cisplatin, or UUO were used to investigate its role in AKI. We established cellular models with overexpression or knockout of ISG15 and subjected them to hypoxia-reoxygenation, cisplatin, or transforming growth factor- ß1 (TGF-ß1) stimulation. Renal RNA-seq data obtained from AKI models sourced from public databases and our studies, were utilized to examine the expression profiles of ISG15 and its associated genes. Additionally, published single cell RNA-seq data from human kidney allograft biopsies and mouse IRI model were analyzed to investigate the expression patterns of ISG15 and the type I TGF-ß receptor (TGFßR1). Western blotting, qPCR, co-immunoprecipitation, and immunohistochemical staining assays were performed to validate our findings. Results: Alleviated pathological injury and renal function were observed in Isg15 KO mice with IRI-, cisplatin-, or UUO-induced AKI and the following AKI-to-CKD transition. In hypoxia-reoxygenation, cisplatin or TGF-ß1 treated HK-2 cells, knockout ISG15 reduced stimulus-induced cell fibrosis, while overexpression of ISG15 with modification capacity exacerbated cell fibrosis. Immunoprecipitation assays demonstrated that ISG15 promoted ISGylation of TGFßR1, and inhibited its ubiquitination. Moreover, knockout of TGFßR1 blocked ISG15's fibrosis-exacerbating effect in HK-2 cells, while overexpression of TGFßR1 abolished the renal protective effect of ISG15 knockout during IRI-induced kidney injury. Conclusions: ISG15 plays an important role in the development of AKI and subsequent AKI-to-CKD transition by promoting TGFßR1 ISGylation.
Asunto(s)
Lesión Renal Aguda , Cisplatino , Citocinas , Ratones Noqueados , Daño por Reperfusión , Ubiquitinas , Animales , Humanos , Masculino , Ratones , Lesión Renal Aguda/metabolismo , Lesión Renal Aguda/genética , Lesión Renal Aguda/patología , Cisplatino/farmacología , Citocinas/metabolismo , Modelos Animales de Enfermedad , Riñón/metabolismo , Riñón/patología , Ratones Endogámicos C57BL , Receptor Tipo I de Factor de Crecimiento Transformador beta/metabolismo , Receptor Tipo I de Factor de Crecimiento Transformador beta/genética , Insuficiencia Renal Crónica/metabolismo , Insuficiencia Renal Crónica/genética , Insuficiencia Renal Crónica/patología , Daño por Reperfusión/metabolismo , Daño por Reperfusión/genética , Daño por Reperfusión/patología , Factor de Crecimiento Transformador beta1/metabolismo , Factor de Crecimiento Transformador beta1/genética , Ubiquitinas/metabolismo , Ubiquitinas/genética , Obstrucción Ureteral/metabolismo , Obstrucción Ureteral/complicaciones , Obstrucción Ureteral/genéticaRESUMEN
Chronic kidney disease (CKD) is a progressive disorder associated with a decline in kidney function. Consequently, patients with advanced stages of CKD require renal replacement therapies, such as dialysis and kidney transplantation. Various conditions lead to the development of CKD, including diabetes mellitus, hypertension, and glomerulonephritis, among others. The disease is associated with metabolic and hormonal dysregulation, including uraemia and hyperparathyroidism, as well as with low-grade systemic inflammation. Altered homeostasis increases the risk of developing severe comorbidities, such as cardiovascular diseases or sarcopenia, which increase mortality. Sarcopenia is defined as a progressive decline in muscle mass and function. However, the precise mechanisms that link CKD and the development of sarcopenia are poorly understood. Knowledge about these linking mechanisms might lead to the introduction of precise treatment strategies that could prevent muscle wasting. This review discusses inflammatory mediators, metabolic and hormonal dysregulation, gut microbiota dysbiosis, and non-coding RNA alterations that could link CKD and sarcopenia.
Asunto(s)
Disbiosis , Microbioma Gastrointestinal , Inflamación , MicroARNs , Insuficiencia Renal Crónica , Sarcopenia , Sarcopenia/metabolismo , Humanos , Insuficiencia Renal Crónica/metabolismo , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/patología , Insuficiencia Renal Crónica/microbiología , MicroARNs/genética , MicroARNs/metabolismo , Inflamación/metabolismo , AnimalesRESUMEN
Acute kidney injury (AKI) causes epithelial damage followed by subsequent repair. While successful repair restores kidney function, this process is often incomplete and can lead to chronic kidney disease (CKD) in a process called failed repair. To better understand the epigenetic reprogramming driving this AKI-to-CKD transition, we generated a single-nucleus multiomic atlas for the full mouse AKI time course, consisting of ~280,000 single-nucleus transcriptomes and epigenomes. We reveal cell-specific dynamic alterations in gene regulatory landscapes reflecting, especially, activation of proinflammatory pathways. We further generated single-nucleus multiomic data from four human AKI samples including validation by genome-wide identification of nuclear factor κB binding sites. A regularized regression analysis identifies key regulators involved in both successful and failed repair cell fate, identifying the transcription factor CREB5 as a regulator of both successful and failed tubular repair that also drives proximal tubular cell proliferation after injury. Our interspecies multiomic approach provides a foundation to comprehensively understand cell states in AKI.
Asunto(s)
Lesión Renal Aguda , Epigénesis Genética , Lesión Renal Aguda/genética , Lesión Renal Aguda/metabolismo , Lesión Renal Aguda/patología , Animales , Ratones , Humanos , Transcriptoma , FN-kappa B/metabolismo , FN-kappa B/genética , Modelos Animales de Enfermedad , Reprogramación Celular/genética , Proliferación Celular/genética , Insuficiencia Renal Crónica/genética , Insuficiencia Renal Crónica/patología , Insuficiencia Renal Crónica/metabolismoRESUMEN
BACKGROUND: The prevalence of chronic kidney disease (CKD) is on the rise, posing a significant public health challenge. Although gut microbiome dysbiosis has been implicated in the impairment of kidney functions, the existence of pathological subtypes-linked differences remains largely unknown. We aimed to characterize the intestinal microbiota in patients with membranous nephropathy (MN), IgA nephropathy (IgAN), minimal change disease (MCD), and ischemic renal injury (IRI) in order to investigate the intricate relationship between intestinal microbiota and CKD across different subtypes. METHODS: We conducted a cross-sectional study involving 94 patients with various pathological patterns of CKD and 54 healthy controls (HCs). The clinical parameters were collected, and stool samples were obtained from each participant. Gut microbial features were analyzed using 16S rRNA sequencing and taxon annotation to compare the HC, CKD, MN, IgAN, MCD, and IRI groups. RESULTS: The CKD subjects exhibited significantly reduced alpha diversity, modified community structures, and disrupted microbial composition and potential functions compared to the control group. The opportunistic pathogen Klebsiella exhibited a significant enrichment in patients with CKD, whereas Akkermansia showed higher abundance in HCs. The study further revealed the presence of heterogeneity in intestinal microbial signatures across diverse CKD pathological types, including MN, IgAN, MCD, and IRI. The depression of the family Lachnospiraceae and the genus Bilophila was prominently observed exclusively in patients with MN, while suppressed Streptococcus was detected only in individuals with MCD, and a remarkable expansion of the genus Escherichia was uniquely found in cases of IRI. The study also encompassed the development of classifiers employing gut microbial diagnostic markers to accurately discriminate between distinct subtypes of CKD. CONCLUSIONS: The dysregulation of gut microbiome was strongly correlated with CKD, exhibiting further specificity towards distinct pathological patterns. Our study emphasizes the significance of considering disease subtypes when assessing the impact of intestinal microbiota on the development, diagnosis, and treatment of CKD.
Asunto(s)
Microbioma Gastrointestinal , Insuficiencia Renal Crónica , Humanos , Insuficiencia Renal Crónica/microbiología , Insuficiencia Renal Crónica/patología , Masculino , Femenino , Persona de Mediana Edad , Estudios de Casos y Controles , Adulto , ARN Ribosómico 16S/genética , Estudios Transversales , Disbiosis/microbiología , Disbiosis/complicaciones , Heces/microbiologíaRESUMEN
Excessive activation of the mineralocorticoid receptor (MR) is implicated in cardiovascular and renal disease. Decreasing MR activation with MR antagonists (MRA) is effective to slow chronic kidney disease (CKD) progression and its cardiovascular comorbidities in animal models and patients. The present study evaluates the effects of the MR modulator balcinrenone and the MRA eplerenone on kidney damage in a metabolic CKD mouse model combining nephron reduction and a 60% high-fat diet. Balcinrenone and eplerenone prevented the progression of renal damages, extracellular matrix remodeling and inflammation to a similar extent. We identified a novel mechanism linking MR activation to the renal proteoglycan deposition and inflammation via the TLR4 pathway activation. Balcinrenone and eplerenone similarly blunted this pathway activation.
Asunto(s)
Eplerenona , Matriz Extracelular , Ratones Endogámicos C57BL , Antagonistas de Receptores de Mineralocorticoides , Proteoglicanos , Receptores de Mineralocorticoides , Transducción de Señal , Receptor Toll-Like 4 , Animales , Antagonistas de Receptores de Mineralocorticoides/farmacología , Antagonistas de Receptores de Mineralocorticoides/uso terapéutico , Receptor Toll-Like 4/metabolismo , Eplerenona/farmacología , Eplerenona/uso terapéutico , Receptores de Mineralocorticoides/metabolismo , Matriz Extracelular/metabolismo , Matriz Extracelular/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Masculino , Proteoglicanos/metabolismo , Espironolactona/farmacología , Espironolactona/análogos & derivados , Insuficiencia Renal Crónica/tratamiento farmacológico , Insuficiencia Renal Crónica/metabolismo , Insuficiencia Renal Crónica/patología , Modelos Animales de Enfermedad , Riñón/efectos de los fármacos , Riñón/metabolismo , Riñón/patología , Ratones , Inflamación/metabolismo , Inflamación/tratamiento farmacológicoRESUMEN
BACKGROUND: Eplerenone is a selective aldosterone receptor blocker that is effective in preventing the progression of chroinic kidney disease (CKD). However, its mechanism and role in CKD pregnancy still remain uncertain. The aim of this study was to evaluate whether eplerenone could attenuated the fibrosis of unilateral ureteral obstruction (UUO) pregnant rats' contralateral kidney, improved pregnancy outcome and explore its therapeutic mechanisms. METHODS: A pregnancy rat model of UUO established, female Wistar rats were randomly assigned into sham-operated group (Sham group),sham-operated combined pregnancy group (SP group), unilateral ureteral obstruction combined pregnancy group (UUO + Pregnancy group), unilateral ureteral obstruction combined pregnancy, administered eplerenone (UUO + Pregnancy+Eplerenone group). On the 18th day of pregnancy, the rats were placed in a metabolic cage, 24 h urine was collected and stored at -80 °C. Next day, all animals were euthanized, and serum was collected by centrifugation and stored at -20 °C. Then the right kidney was extracted, a part of the kidney was placed in 4% paraformaldehyde for morphology, immunohistochemical staining, and immunofluorescence staining, and the other part was placed in a - 80 °C refrigerator for RNA and protein extraction. In vitro, HUVECs was treated with aldosterone, progesterone and estradiol, VEGFA and its receptor blocker bevacizumab. The ability of proliferation, migration and tubularization of HUVECs was detected by CCK-8, scratch wound assay and endothelial tube formation assay. And the co-expression of CD34 and α-SMA of HUVECs was detected by Flow cytometry. RESULTS: Immunofluorescence results showed that the co-expression of CD34 and α-SMA increased in the UUO + Pregnancy group was significantly increased. The expression of SGK-1, TGFß-1, Smad2, Smad3, VEGF-A, VEGFR2, CD34, α-SMA and Collagen I was significantly higher in the kidneys of the UUO + Pregnancy group compared to the Sham group and SP group. Eplerenone inhibited the expression of those results. In vitro, the ability of proliferation, migration and tubularization was increased after treated with aldosterone, aldosterone with progesterone and estradiol or VEGFA. Similarly, the expression of α-SMA on the surface of HUVECs treated with aldosterone, aldosterone with progesterone and estradiol were increased, while eplerenone supressed its expression. CONCLUSION: Eplerenone inhibits renal angiogenesis by blocking the SGK-1/TGFß signal transduction pathway, thereby inhibiting the phenotypic transformation of endothelial cells, slowing down renal fibrosis, and reducing kidney damage caused by pregnancy.
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Eplerenona , Proteínas Inmediatas-Precoces , Riñón , Proteínas Serina-Treonina Quinasas , Ratas Wistar , Insuficiencia Renal Crónica , Factor de Crecimiento Transformador beta , Animales , Femenino , Embarazo , Eplerenona/farmacología , Eplerenona/uso terapéutico , Ratas , Proteínas Inmediatas-Precoces/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Insuficiencia Renal Crónica/metabolismo , Insuficiencia Renal Crónica/tratamiento farmacológico , Insuficiencia Renal Crónica/patología , Riñón/metabolismo , Riñón/patología , Riñón/efectos de los fármacos , Factor de Crecimiento Transformador beta/metabolismo , Transducción de Señal/efectos de los fármacos , Humanos , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Proliferación Celular/efectos de los fármacos , Espironolactona/farmacología , Espironolactona/análogos & derivados , Espironolactona/uso terapéutico , Obstrucción Ureteral/metabolismo , Obstrucción Ureteral/tratamiento farmacológico , Obstrucción Ureteral/patología , Obstrucción Ureteral/complicaciones , Antagonistas de Receptores de Mineralocorticoides/farmacología , Antagonistas de Receptores de Mineralocorticoides/uso terapéutico , Factor A de Crecimiento Endotelial Vascular/metabolismo , Movimiento Celular/efectos de los fármacos , Neovascularización Patológica/metabolismo , Neovascularización Patológica/tratamiento farmacológico , AngiogénesisRESUMEN
Hyperuricemic nephropathy (HN) is a global metabolic disorder characterized by uric acid (UA) metabolism dysfunction, resulting in hyperuricemia (HUA) and tubulointerstitial fibrosis (TIF). Sodium-dependent glucose transporter 2 inhibitor, dapagliflozin, has shown potential in reducing serum UA levels in patients with chronic kidney disease (CKD), though its protective effects against HN remain uncertain. This study investigates the functional, pathological, and molecular changes in HN through histological, biochemical, and transcriptomic analyses in patients, HN mice, and UA-stimulated HK-2 cells. Findings indicate UA-induced tubular dysfunction and fibrotic activation, which dapagliflozin significantly mitigates. Transcriptomic analysis identifies estrogen-related receptor α (ERRα), a downregulated transcription factor in HN. ERRα knockin mice and ERRα-overexpressed HK-2 cells demonstrate UA resistance, while ERRα inhibition exacerbates UA effects. Dapagliflozin targets ERRα, activating the ERRα-organic anion transporter 1 (OAT1) axis to enhance UA excretion and reduce TIF. Furthermore, dapagliflozin ameliorates renal fibrosis in non-HN CKD models, underscoring the therapeutic significance of the ERRα-OAT1 axis in HN and CKD.
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Compuestos de Bencidrilo , Fibrosis , Glucósidos , Hiperuricemia , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Animales , Glucósidos/farmacología , Glucósidos/uso terapéutico , Compuestos de Bencidrilo/farmacología , Fibrosis/tratamiento farmacológico , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Hiperuricemia/tratamiento farmacológico , Hiperuricemia/complicaciones , Humanos , Ratones , Masculino , Receptor Relacionado con Estrógeno ERRalfa , Enfermedades Renales/tratamiento farmacológico , Enfermedades Renales/patología , Enfermedades Renales/metabolismo , Riñón/patología , Riñón/efectos de los fármacos , Riñón/metabolismo , Ratones Endogámicos C57BL , Ácido Úrico/sangre , Receptores de Estrógenos/metabolismo , Proteína 1 de Transporte de Anión Orgánico/metabolismo , Proteína 1 de Transporte de Anión Orgánico/genética , Línea Celular , Insuficiencia Renal Crónica/tratamiento farmacológico , Insuficiencia Renal Crónica/patología , Modelos Animales de Enfermedad , FemeninoRESUMEN
Chronic kidney disease (CKD) and end-stage renal disease (ESRD) are prevalent and debilitating conditions with a significant impact on patients' quality of life. In this study, we conducted a comprehensive investigation into the histological characteristics of renal progenitor/stem cells (RPCs), renal mesenchymal stem-like cells, and endothelial progenitor cells (EPCs) in CKD and ESRD patients. Additionally, we performed a molecular docking analysis to explore potential drug-receptor interactions involving common medications prescribed to CKD patients. Our histological examination revealed a noteworthy increase in the number of CD24- and CD133-positive cells in CKD and ESRD patients, representing RPCs. These cells are implicated in kidney repair and regeneration, underscoring their potential role in CKD management. Moreover, we observed an elevation in the number of EPCs within the kidneys of CKD and ESRD patients, suggesting a protective role of EPCs in kidney preservation. The molecular docking analysis unveiled intriguing insights into potential drug interventions. Notably, digoxin exhibited the highest in-silico binding affinity to numerous receptors associated with the functions of RPCs, renal mesenchymal stem-like cells, and EPCs, emphasizing the potential multifaceted effects of this cardiac glycoside in CKD patients. Other drugs, including apixaban, glimepiride, and glibenclamide, also displayed strong in-silico affinities to specific receptors, indicating their potential influence on various renal cell functions. In conclusion, this study provides valuable insights into the histological alterations in renal cell populations in CKD and ESRD patients and underscores the potential roles of RPCs and EPCs in kidney repair and preservation. The molecular docking analysis reveals the complex interactions between common drugs and renal cells, suggesting the need for further in-vitro and in-vivo research to fully understand these relationships. These findings contribute to our understanding of CKD and offer new avenues for research into potential therapeutic interventions.
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Células Progenitoras Endoteliales , Fallo Renal Crónico , Células Madre Mesenquimatosas , Simulación del Acoplamiento Molecular , Insuficiencia Renal Crónica , Humanos , Células Madre Mesenquimatosas/metabolismo , Células Madre Mesenquimatosas/patología , Insuficiencia Renal Crónica/patología , Insuficiencia Renal Crónica/metabolismo , Fallo Renal Crónico/patología , Fallo Renal Crónico/metabolismo , Células Progenitoras Endoteliales/metabolismo , Células Progenitoras Endoteliales/patología , Riñón/patología , Riñón/metabolismo , Masculino , Femenino , Persona de Mediana Edad , Anciano , AdultoRESUMEN
Bombesin receptor-activated protein (BRAP), encoded by the C6orf89 gene in humans, is expressed in various cells with undefined functions. BC004004, the mouse homologue of C6orf89, has been shown to play a role in bleomycin-induced pulmonary fibrosis through the use of a BC004004 gene knockout mouse (BC004004-/-). In this study, we investigated the potential involvement of BRAP in renal fibrosis using two mouse models: unilateral ureteral obstruction (UUO) and type 2 diabetes mellitus induced by combination of a high-fat diet (HFD) and streptozocin (STZ). BRAP or its homologue was expressed in tubular epithelial cells (TECs) in the kidneys of patients with chronic kidney disease (CKD) and in BC004004+/+ mice. Compared to control mice, BC004004-/- mice exhibited attenuated renal injury and renal fibrosis after UUO or after HFD/STZ treatment. Immunohistochemistry and immunoblot analyses of the kidneys of BC004004+/+ mice after UUO surgery showed a more significant decrease in E-cadherin expression and a more significant increase in both α smooth muscle actin (α-SMA) and vimentin expression compared to BC004004-/- mice. Additionally, stimulation with transforming growth factor-ß1 (TGF-ß1) led to a more significant decrease in E-cadherin expression and a more significant increase in α-SMA and vimentin expression in isolated TECs from BC004004+/+ than in those from BC004004-/- mice. These results suggest that an enhanced epithelial-mesenchymal transition (EMT) process occurred in TECs in BC004004+/+ mice during renal injury, which might contribute to renal fibrosis. The loss of the BRAP homologue in BC004004-/- mice suppressed EMT activation in kidneys and contributed to the suppression of fibrosis during renal injury.
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Fibrosis , Animales , Ratones , Masculino , Humanos , Transición Epitelial-Mesenquimal , Ratones Noqueados , Obstrucción Ureteral/patología , Obstrucción Ureteral/complicaciones , Riñón/patología , Riñón/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Actinas/metabolismo , Ratones Endogámicos C57BL , Cadherinas/metabolismo , Cadherinas/genética , Insuficiencia Renal Crónica/patología , Insuficiencia Renal Crónica/metabolismo , Insuficiencia Renal Crónica/genética , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patología , Diabetes Mellitus Tipo 2/genéticaRESUMEN
Accumulated evidence suggested that gut microbial dysbiosis interplayed with progressive chronic kidney disease (CKD). However, no available therapy is effective in suppressing progressive CKD. Here, using microbiomics in 480 participants including healthy controls and patients with stage 1-5 CKD, we identified an elongation taxonomic chain Bacilli-Lactobacillales-Lactobacillaceae-Lactobacillus-Lactobacillus johnsonii correlated with patients with CKD progression, whose abundance strongly correlated with clinical kidney markers. L. johnsonii abundance reduced with progressive CKD in rats with adenine-induced CKD. L. johnsonii supplementation ameliorated kidney lesion. Serum indole-3-aldehyde (IAld), whose level strongly negatively correlated with creatinine level in CKD rats, decreased in serum of rats induced using unilateral ureteral obstruction (UUO) and 5/6 nephrectomy (NX) as well as late CKD patients. Treatment with IAld dampened kidney lesion through suppressing aryl hydrocarbon receptor (AHR) signal in rats with CKD or UUO, and in cultured 1-hydroxypyrene-induced HK-2 cells. Renoprotective effect of IAld was partially diminished in AHR deficiency mice and HK-2 cells. Our further data showed that treatment with L. johnsonii attenuated kidney lesion by suppressing AHR signal via increasing serum IAld level. Taken together, targeting L. johnsonii might reverse patients with CKD. This study provides a deeper understanding of how microbial-produced tryptophan metabolism affects host disease and discovers potential pathways for prophylactic and therapeutic treatments for CKD patients.
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Lactobacillus johnsonii , Insuficiencia Renal Crónica , Insuficiencia Renal Crónica/microbiología , Insuficiencia Renal Crónica/terapia , Insuficiencia Renal Crónica/patología , Animales , Ratas , Humanos , Ratones , Masculino , Lactobacillus johnsonii/genética , Indoles , Receptores de Hidrocarburo de Aril/genética , Receptores de Hidrocarburo de Aril/metabolismo , Microbioma Gastrointestinal , FemeninoRESUMEN
Chronic kidney disease (CKD) is associated with renal lipid dysmetabolism among a variety of other pathways. We recently demonstrated that oxysterol-binding protein-like 7 (OSBPL7) modulates the expression and function of ATP-binding cassette subfamily A member 1 (ABCA1) in podocytes, a specialized type of cell essential for kidney filtration. Drugs that target OSBPL7 lead to improved renal outcomes in several experimental models of CKD. However, the role of OSBPL7 in podocyte injury remains unclear. Using mouse models and cellular assays, we investigated the influence of OSBPL7 deficiency on podocytes. We demonstrated that reduced renal OSBPL7 levels as observed in two different models of experimental CKD are linked to increased podocyte apoptosis, primarily mediated by heightened endoplasmic reticulum (ER) stress. Although as expected, the absence of OSBPL7 also resulted in lipid dysregulation (increased lipid droplets and triglycerides content), OSBPL7 deficiency-related lipid dysmetabolism did not contribute to podocyte injury. Similarly, we demonstrated that the decreased autophagic flux we observed in OSBPL7-deficient podocytes was not the mechanistic link between OSBPL7 deficiency and apoptosis. In a complementary zebrafish model, osbpl7 knockdown was sufficient to induce proteinuria and morphological damage to the glomerulus, underscoring its physiological relevance. Our study sheds new light on the mechanistic link between OSBPL7 deficiency and podocyte injury in glomerular diseases associated with CKD, and it strengthens the role of OSBPL7 as a novel therapeutic target.NEW & NOTEWORTHY OSBPL7 and ER stress comprise a central mechanism in glomerular injury. This study highlights a crucial link between OSBPL7 deficiency and ER stress in CKD. OSBPL7 deficiency causes ER stress, leading to podocyte apoptosis. There is a selective effect on lipid homeostasis in that OSBPL7 deficiency affects lipid homeostasis, altering cellular triglyceride but not cholesterol content. The interaction of ER stress and apoptosis supports that ER stress, not reduced autophagy, is the main driver of apoptosis in OSBPL7-deficient podocytes.