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As life expectancy continues to increase, age-related kidney diseases are becoming more prevalent. Chronic kidney disease (CKD) is not only a consequence of aging but also a potential accelerator of aging process. Here we report the pivotal role of podocyte ERCC1, a DNA repair factor, in maintaining glomerular integrity and a potential effect on multiple organs. Podocyte-specific ERCC1-knockout mice developed severe proteinuria, glomerulosclerosis, and renal failure, accompanied by a significant increase in glomerular DNA single-strand breaks (SSBs) and double-strand breaks (DSBs). ERCC1 gene transfer experiment in the knockout mice attenuated proteinuria and glomerulosclerosis with reduced DNA damage. Notably, CD44+CD8+ memory T cells, indicative of T-cell senescence, were already elevated in the peripheral blood of knockout mice at 10 weeks old. Additionally, levels of senescence-associated secretory phenotype (SASP) factors were significantly increased in both the circulation and multiple organs of the knockout mice. In older mice and human patients, we observed an accumulation of DSBs and an even greater buildup of SSBs in glomeruli, despite no significant reduction in ERCC1 expression with age in mice. Collectively, our findings highlight the crucial role of ERCC1 in repairing podocyte DNA damage, with potential implications for inflammation in various organs.
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Enfermedades Renales , Podocitos , Humanos , Ratones , Animales , Podocitos/metabolismo , Glomérulos Renales/metabolismo , Enfermedades Renales/metabolismo , Ratones Noqueados , Proteinuria/genética , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Endonucleasas/genética , Endonucleasas/metabolismoRESUMEN
BACKGROUND: Exit-site infection (ESI) is a common recurring complication in patients undergoing peritoneal dialysis (PD). Sucrose and povidone-iodine (SPI) mixtures, antimicrobial ointments that promote wound healing, have been used for the treatment of ulcers and burns, but their efficacy in exit-site care is still unclear. METHODS: This single-center retrospective observational study included patients who underwent PD between May 2010 and June 2022 and presented with episodes of ESI. Patients were divided into SPI and non-SPI groups and followed up from initial ESI onset until PD cessation, death, transfer to another facility, or June 2023. RESULTS: Among the 82 patients (mean age 62, [54-72] years), 23 were treated with SPI. The median follow-up duration was 39 months (range, 14-64), with an overall ESI incidence of 0.70 episodes per patient-year. Additionally, 43.1% of second and 25.6% of third ESI were caused by the same pathogen as the first. The log-rank test demonstrated significantly better second and third ESI-free survival in the SPI group than that in the non-SPI group (p < 0.01 and p < 0.01, respectively). In a Cox regression analysis, adjusting for potential confounders, SPI use was a significant predictor of decreased second and third ESI episodes (hazard ratio [HR], 0.22; 95% confidence interval [CI], 0.10-0.52 and HR, 0.22; 95%CI, 0.07-0.73, respectively). CONCLUSIONS: Our results showed that the use of SPI may be a promising option for preventing the incidence of ESI in patients with PD. TRIAL REGISTRATION: This study was approved by the Keio University School of Medicine Ethics Committee (approval number 20231078) on August 28, 2023. Retrospectively registered.
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Antiinfecciosos Locales , Infecciones Relacionadas con Catéteres , Diálisis Peritoneal , Povidona Yodada , Sacarosa , Humanos , Povidona Yodada/uso terapéutico , Persona de Mediana Edad , Estudios Retrospectivos , Masculino , Femenino , Anciano , Antiinfecciosos Locales/uso terapéutico , Infecciones Relacionadas con Catéteres/prevención & control , Infecciones Relacionadas con Catéteres/etiología , Catéteres de Permanencia/efectos adversos , Resultado del TratamientoRESUMEN
The DNA repair system is essential for the maintenance of genome integrity and is mainly investigated in the areas of aging and cancer. The DNA repair system is strikingly cell-type specific, depending on the expression of DNA repair factors; therefore, different DNA repair systems may exist in each type of kidney cell. Importance of DNA repair in the kidney is suggested by renal phenotypes caused by both genetic mutations in the DNA repair pathway and increased stimuli of DNA damage. Recently, we reported the importance of DNA double-strand break repair in glomerular podocytes and its involvement in the alteration of DNA methylation status, which regulates podocyte phenotypes. In this review, we summarize the roles of the DNA repair system in the kidneys and possible associations with altered kidney DNA methylation, which have been infrequently reported together. Investigations of DNA damage repair and epigenetic changes in the kidneys may achieve a profound understanding of kidney aging and diseases.
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Envejecimiento/genética , Metilación de ADN , Reparación del ADN , Enfermedades Renales/genética , Riñón/patología , Animales , Modelos Animales de Enfermedad , Epigénesis Genética , Humanos , Riñón/fisiopatología , Enfermedades Renales/patología , Enfermedades Renales/fisiopatología , MutaciónRESUMEN
AIMS: Remote monitoring (RM) can improve management of chronic diseases. We evaluated the impact of RM in automated peritoneal dialysis (APD) in a simulation study. MATERIALS AND METHODS: We simulated 12 patient scenarios with common clinical problems and estimated the likely healthcare resource consumption with and without the availability of RM (RM+ and RM- groups, respectively). Scenarios were evaluated 4 times by randomly allocated nephrologist-nurse teams or nephrologist-alone assessors. RESULTS: The RM+ group was assessed as having significantly lower total healthcare resource consumption compared with the RM- group (36.8 vs. 107.5 total episodes of resource consumption, p = 0.002). The RM+ group showed significantly lower "unplanned hospital visits" (2.3 vs. 11.3, p = 0.005), "emergency room visits" (0.5 vs. 5.3, p = 0.003), "home visits" (0.5 vs. 5.8, p = 0.016), "exchanges over the telephone" (18.5 vs. 57.8, p = 0.002), and "change to hemodialysis" (0.5 vs. 2.5, p = 0.003). Evaluations did not differ between nephrologist-nurse teams vs. nephrologist-alone assessors. CONCLUSION: RM can be expected to reduce healthcare resource consumption in APD patients.â©.
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Diálisis Peritoneal , Telemedicina , Manejo de la Enfermedad , Humanos , Diálisis Peritoneal/economía , Diálisis Peritoneal/estadística & datos numéricos , Insuficiencia Renal Crónica/terapia , Telemedicina/economía , Telemedicina/métodos , Telemedicina/estadística & datos numéricosRESUMEN
The growing number of patients with chronic kidney disease (CKD) is recognized as an emerging problem worldwide. Recent studies have indicated that deregulation of transcription factors is associated with the onset or progression of kidney disease. Several clinical trials indicated that regression of CKD may be feasible via activation of the transcription factor nuclear factor erythroid-2 related factor 2 (Nrf2), which suggests that transcription factors may be potential drug targets for CKD. Agents stabilizing hypoxia-inducible factor (HIF), which may be beneficial for renal anemia and renal protection, are also now under clinical trial. Recently, we have reported that the transcription factor Kruppel-like factor 4 (KLF4) regulates the glomerular podocyte epigenome, and that the antiproteinuric effect of the reninâ»angiotensin system blockade may be partially mediated by KLF4. KLF4 is one of the Yamanaka factors that induces iPS cells and is reported to be involved in epigenetic remodeling. In this article, we summarize the transcription factors associated with CKD and particularly focus on the possibility of transcription factors being novel drug targets for CKD through epigenetic modulation.
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Terapia Molecular Dirigida , Insuficiencia Renal Crónica/tratamiento farmacológico , Factores de Transcripción/metabolismo , Humanos , Factor 4 Similar a Kruppel , Modelos BiológicosRESUMEN
BACKGROUND: Cerebrovascular disease is a major cause of mortality and morbidity. Chronic kidney disease (CKD) is prevalent in stroke patients. This study evaluated the correlation between kidney dysfunction and asymptomatic findings on carotid ultrasonography (US) and brain magnetic resonance imaging (MRI) in a Japanese population with health checkups.MethodsâandâResults:In total, 1,716 subjects aged 40-80 years, who received health checkups from January 1 to December 31, 2015, were included. Common carotid artery intima-media thickness (CCA-IMT) and carotid plaques by US, and the presence of old non-lacunar infarctions, lacunar infarctions, white matter lesions (WMLs), cerebral microbleeds (CMBs), and atrophy by brain MRI were evaluated. After adjusting for cardiovascular risk factors, multiple regression analyses revealed that an eGFR ranging from 15 to 44 mL/min/1.73 m2was independently associated with CCA plaques and hypoechoic or heterogeneous plaques. Proteinuria was associated with CCA or internal carotid artery plaques, the number of carotid plaques, and the presence of old non-lacunar infarctions and CMBs. CONCLUSIONS: Decreased eGFR and proteinuria were independent risk factors for asymptomatic abnormalities on carotid US and brain MRI, which are surrogate markers for cerebrovascular diseases. Evaluation of these abnormalities may be useful for prevention of symptomatic cerebrovascular events in CKD patients.
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Arterias Carótidas/diagnóstico por imagen , Enfermedades de las Arterias Carótidas , Grosor Intima-Media Carotídeo , Enfermedades Renales , Imagen por Resonancia Magnética , Encuestas y Cuestionarios , Enfermedad Aguda , Adulto , Anciano , Anciano de 80 o más Años , Enfermedades de las Arterias Carótidas/complicaciones , Enfermedades de las Arterias Carótidas/diagnóstico por imagen , Enfermedades de las Arterias Carótidas/epidemiología , Femenino , Humanos , Enfermedades Renales/diagnóstico por imagen , Enfermedades Renales/epidemiología , Enfermedades Renales/etiología , Masculino , Persona de Mediana EdadRESUMEN
Antiglomerular basement membrane (GBM) disease has a poor prognosis. The rapid detection of serum anti-GBM antibody using an enzyme immunoassay, which has a high sensitivity and specificity, leads to an early diagnosis and improved prognosis. We report a case of acute kidney injury with false-positive anti-GBM antibody. A man in his early fifties underwent aortic arch replacement using bovine serum albumin (BSA)-containing surgical adhesion. After intravenous administration of vancomycin for a fever, he developed acute kidney injury without an abnormal urinalysis, and his anti-GBM antibody titer (fluorescence enzyme immunoassay [FEIA]) was 70.4 IU/mL. A kidney biopsy showed acute tubular injury and minor glomerular abnormalities without immunoglobulin G deposits, suggesting no evidence of anti-GBM glomerulonephritis. Consistent with the false-positive anti-GBM antibody test results, anti-GBM antibody determined using a chemiluminescent enzyme immunoassay was negative. A serum sample showed crossbinding to the FEIA plate from which the GBM antigen was removed. This finding indicated a nonspecific reaction to BSA, which contains a coating solution for the FEIA plate. This reaction was likely caused by anti-BSA antibody produced using BSA-containing surgical adhesion. Our findings suggest emerging challenges in diagnosing anti-GBM disease. Nephrologists must remain vigilant regarding false-positive anti-GBM antibody test results, particularly in cases evaluated with immunoassays that contain BSA.
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Chronic kidney disease (CKD) is associated with multiple complications, with recent scholarly attention underscoring cognitive impairment as a salient manifestation. Considering societal aging, preserving cognitive function has emerged as an urgent medical concern. Prolonged dialysis, encompassing hemodialysis (HD) and peritoneal dialysis (PD), has been associated with a decline in cognitive function. Here, we present the cases of three patients undergoing PD who exhibited a noticeable improvement in cognitive function upon the initiation of HD. One patient had exhibited mild cognitive decline, whereas the remaining two presented more severe impairment. Apart from a mild tendency for fluid retention, none of the three patients exhibited abnormalities in physical or imaging examinations. Evaluation using the Japanese version of the Montreal Cognitive Assessment (MoCA-J) yielded decreased scores across multiple domains, notably in executive and attention functions. However, after HD initiation, all patients demonstrated a marked enhancement in multiple MoCA-J parameters, accompanied by a significant improvement in subjective symptoms. Moreover, improvements in anemia and hypoalbuminemia were observed in all three patients, whereas consistent trends in other parameters were absent. These clinical observations suggest that the integration of HD into the therapeutic regimen of patients undergoing PD may enhance cognitive function, highlighting the contributory roles of hemoglobin and albumin in CKD-associated cognitive impairment.
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Recent reports have shown the feasibility of measuring biological age from DNA methylation levels in blood cells from specific regions identified by machine learning, collectively known as the epigenetic clock or DNA methylation clock. While extensive research has explored the association of the DNA methylation clock with cardiovascular diseases, cancer, and Alzheimer's disease, its relationship with kidney diseases remains largely unexplored. In particular, it is unclear whether the DNA methylation clock could serve as a predictor of worsening kidney function. In this pilot study involving 20 subjects, we investigated the association between the DNA methylation clock and subsequent deterioration of renal function. Additionally, we noninvasively evaluated DNA damage in urinary shedding cells using a previously reported method to examine the correlation with the DNA methylation clock and worsening kidney function. Our findings revealed that patients with an accelerated DNA methylation clock exhibited increased DNA damage in urinary shedding cells, along with a higher rate of eGFR decline. Moreover, in cases of advanced CKD (G4-5), the DNA damage in urinary shedding cells was significantly increased, highlighting the interplay between elevated DNA damage and eGFR decline. This study suggests the potential role of the DNA methylation clock and urinary DNA damage as predictive markers for the progression of chronic kidney disease.
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Daño del ADN , Metilación de ADN , Tasa de Filtración Glomerular , Insuficiencia Renal Crónica , Humanos , Proyectos Piloto , Masculino , Femenino , Persona de Mediana Edad , Anciano , Insuficiencia Renal Crónica/orina , Insuficiencia Renal Crónica/genética , Insuficiencia Renal Crónica/patología , Progresión de la Enfermedad , Biomarcadores/orina , Riñón/metabolismo , Riñón/patología , Epigénesis GenéticaRESUMEN
The number of chronic kidney disease (CKD) patients is increasing worldwide, and it is necessary to diagnose CKD patients in earlier stages to improve their prognosis. Previously, in a study using human samples, we reported that DNA methylation and DNA damage in podocytes are potential markers for kidney function decline in IgA nephropathy; however, these candidate markers have not been adequately investigated in other glomerular diseases. Here, we report that the association of podocyte DNA damage and DNA methylation with eGFR decline and proteinuria differs depending on the type of glomerular disease. Patients diagnosed with minor glomerular abnormality (MGA, n = 33), membranous nephropathy (MN, n = 9) or diabetic nephropathy (DN, n = 10) following kidney biopsy at Keio University Hospital from 2015 to 2017 were included. In MGA patients, both podocyte DNA damage and glomerular DNA methylation were associated with the severity of proteinuria. In DN patients, podocyte DNA double-strand breaks (DSBs) and glomerular DNA methylation were associated with an eGFR decline. When patients with urinary protein levels of more than 1 g/gCr were examined, fewer podocyte DNA DSBs were detected in MN patients than in MGA patients, and the level of glomerular DNA methylation was lower in MN patients than in MGA or DN patients. These results indicate that investigating podocyte DNA DSBs and DNA methylation changes may be useful for understanding the pathogenesis of CKD with proteinuria in humans. This study suggested the association of podocyte DNA damage and subsequent DNA methylation with proteinuria in minor glomerular abnormalities (MGA) patients and those with eGFR declines in diabetic nephropathy (DN) patients, respectively.
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Nefropatías Diabéticas , Podocitos , Insuficiencia Renal Crónica , Humanos , Podocitos/metabolismo , Nefropatías Diabéticas/genética , Metilación de ADN , Proteinuria/genética , Daño del ADN , Insuficiencia Renal Crónica/genética , Insuficiencia Renal Crónica/complicaciones , ADNRESUMEN
Coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains a global pandemic. Although several vaccines targeting SARS-CoV-2 spike proteins protect against COVID-19 infection, mutations affecting virus transmissibility and immune evasion potential have reduced their efficacy, leading to the need for a more efficient strategy. Available clinical evidence regarding COVID-19 suggests that endothelial dysfunction with thrombosis is a central pathogenesis of progression to systemic disease, in which overexpression of plasminogen activator inhibitor-1 (PAI-1) may be important. Here we developed a novel peptide vaccine against PAI-1 and evaluated its effect on lipopolysaccharide (LPS)-induced sepsis and SARS-CoV-2 infection in mice. Administration of LPS and mouse-adapted SARS-CoV-2 increased serum PAI-1 levels, although the latter showed smaller levels. In an LPS-induced sepsis model, mice immunized with PAI-1 vaccine showed reduced organ damage and microvascular thrombosis and improved survival compared with vehicle-treated mice. In plasma clot lysis assays, vaccination-induced serum IgG antibodies were fibrinolytic. However, in a SARS-CoV-2 infection model, survival and symptom severity (i.e., body weight reduction) did not differ between vaccine- and vehicle-treated groups. These results indicate that although PAI-1 may promote the severity of sepsis by increasing thrombus formation, it might not be a major contributor to COVID-19 exacerbation.
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COVID-19 , Inhibidor 1 de Activador Plasminogénico , Sepsis , Animales , Ratones , Anticuerpos Antivirales , Modelos Animales de Enfermedad , Lipopolisacáridos , SARS-CoV-2RESUMEN
Recent epigenome-wide studies suggest an association between blood DNA methylation and kidney function. However, the pathological importance remains unclear. Here, we show that the homing endonuclease I-PpoI-induced DNA double-strand breaks in kidney glomerular podocytes cause proteinuria, glomerulosclerosis, and tubulointerstitial fibrosis with DNA methylation changes in blood cells as well as in podocytes. Single-cell RNA-sequencing analysis reveals an increase in cytotoxic CD8+ T cells with the activating/costimulatory receptor NKG2D in the kidneys, which exhibit a memory precursor effector cell phenotype, and the CD44high memory CD8+ T cells are also increased in the peripheral circulation. NKG2D blockade attenuates the renal phenotype caused by podocyte DNA damage. Blood methylome shows increased DNA methylation in binding sites for STAT1, a transcription factor contributing to CD8+ T cell homeostasis. Collectively, podocyte DNA damage alters the blood methylome, leading to changes in CD8+ T cells, which contribute to sustained renal injury in chronic kidney disease.
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Podocitos , Insuficiencia Renal Crónica , Humanos , Podocitos/metabolismo , Metilación de ADN/genética , Linfocitos T CD8-positivos/metabolismo , Subfamilia K de Receptores Similares a Lectina de Células NK/metabolismo , Riñón/metabolismo , Proteinuria/genética , Proteinuria/metabolismo , Proteinuria/patología , Insuficiencia Renal Crónica/patología , Daño del ADN , ADN/metabolismoRESUMEN
There is a critical need for efficient treatment of chronic kidney disease (CKD). Renal fibrosis is a final common pathway to end-stage renal disease independent of the underlying etiology, and connective tissue growth factor (CTGF) is a well-recognized profibrotic factor in fibrosis of various organ systems. Here, we developed a novel peptide vaccine against CTGF to attenuate the development of renal fibrosis. Three inoculations with this CTGF vaccine at 2-week intervals elicited antibodies specifically binding to human full-length CTGF, and the antigen-specific serum IgG antibody titers were maintained for > 30 weeks. The efficacy of the CTGF vaccine on renal fibrosis was evaluated in adenine-induced CKD and unilateral ureteral obstruction (UUO) murine models. In adenine-induced CKD model, immunization with the CTGF vaccine attenuated renal interstitial fibrosis. Vaccinated mice showed low levels of serum creatinine and urea nitrogen and low urine albumin-creatinine ratio compared with vehicle-treated mice. In UUO model, the CTGF vaccination also suppressed the onset of renal fibrosis. In an in vitro study, CTGF vaccine-elicited IgG antibodies efficiently suppressed CTGF-induced- and transforming growth factor-ß-induced α-smooth muscle actin expression in kidney fibroblasts. These results demonstrate that the CTGF vaccine is a promising strategy to attenuate the development of renal fibrosis.
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Enfermedades Renales , Insuficiencia Renal Crónica , Obstrucción Ureteral , Adenina/metabolismo , Animales , Factor de Crecimiento del Tejido Conjuntivo/metabolismo , Fibrosis , Riñón/metabolismo , Enfermedades Renales/metabolismo , Ratones , Insuficiencia Renal Crónica/complicaciones , Obstrucción Ureteral/patología , Vacunación/efectos adversosRESUMEN
Recently, epigenetic alterations have been shown to be involved in the pathogenesis of diabetes and its complications. Kidney podocytes, which are glomerular epithelial cells, are important cells that form a slit membrane-a barrier for proteinuria. Podocytes are terminally differentiated cells without cell division or replenishment abilities. Therefore, podocyte damage is suggested to be one of the key factors determining renal prognosis. Recent studies, including ours, suggest that epigenetic changes in podocytes are associated with chronic kidney disease, including diabetic nephropathy. Furthermore, the association between DNA damage repair and epigenetic changes in diabetic podocytes has been demonstrated. Detection of podocyte DNA damage and epigenetic changes using human samples, such as kidney biopsy and urine-derived cells, may be a promising strategy for estimating kidney damage and renal prognoses in patients with diabetes. Targeting epigenetic podocyte changes and associated DNA damage may become a novel therapeutic strategy for preventing progression to end-stage renal disease (ESRD) and provide a possible prognostic marker in diabetic nephropathy. This review summarizes recent advances regarding epigenetic changes, especially DNA methylation, in podocytes in diabetic nephropathy and addresses detection of these alterations in human samples. Additionally, we focused on DNA damage, which is increased under high-glucose conditions and associated with the generation of epigenetic changes in podocytes. Furthermore, epigenetic memory in diabetes is discussed. Understanding the role of epigenetic changes in podocytes in diabetic nephropathy may be of great importance considering the increasing diabetic nephropathy patient population in an aging society.
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Effective treatment of diabetic kidney disease (DKD) remains a large unmet medical need. Within the disease's complicated pathogenic mechanism, activation of the advanced glycation end products (AGEs)-receptor for AGE (RAGE) axis plays a pivotal role in the development and progression of DKD. To provide a new therapeutic strategy against DKD progression, we developed a vaccine against RAGE. Three rounds of immunization of mice with the RAGE vaccine successfully induced antigen-specific serum IgG antibody titers and elevated antibody titers were sustained for at least 38 weeks. In addition, RAGE vaccination significantly attenuated the increase in urinary albumin excretion in streptozotocin-induced diabetic mice (type 1 diabetes model) and leptin-receptor-deficient db/db mice (type 2 diabetes model). In microscopic analyses, RAGE vaccination suppressed glomerular hypertrophy and mesangial expansion in both diabetic models and significantly reduced glomerular basement membrane thickness in streptozotocin-induced diabetic mice. Results of an in vitro study indicated that the serum IgG antibody elicited by RAGE vaccination suppressed the expression of AGE-induced vascular cell adhesion molecule 1 and intracellular adhesion molecule 1 in endothelial cells. Thus, our newly developed RAGE vaccine attenuated the progression of DKD in mice and is a promising potential therapeutic strategy for patients with DKD.
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Diabetes Mellitus Experimental/metabolismo , Nefropatías Diabéticas/prevención & control , Receptor para Productos Finales de Glicación Avanzada/inmunología , Vacunación , Animales , Nefropatías Diabéticas/metabolismo , Progresión de la Enfermedad , Masculino , Ratones , Receptor para Productos Finales de Glicación Avanzada/metabolismoRESUMEN
The "preconditioning effect" in AKI is a phenomenon in which an episode of ischemia-reperfusion results in tolerance to subsequent ischemia-reperfusion injury. However, its relationship between DNA damage repair has not been elucidated. Here, we show the role of KAT5 in the preconditioning effect. Preconditioning attenuated DNA damage in proximal tubular cells with elevated KAT5 expression. Ischemia-reperfusion (IR) injuries were exacerbated, and preconditioning effect vanished in proximal tubular-cell-specific KAT5 knockout mice. Investigation of tubuloglomerular feedback (TGF) by MALDI-IMS and urinary adenosine revealed that preconditioning caused attenuated TGF at least in part via KAT5. In addition, K-Cl cotransporter 3 (KCC3) expression decreased in damaged proximal tubular cells, which may be involved in accelerated TGF following IR. Furthermore, KAT5 induced KCC3 expression by maintaining chromatin accessibility and binding to the KCC3 promoter. These results suggest a novel mechanism of the preconditioning effect mediated by the promotion of DNA repair and attenuation of TGF through KAT5.
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BACKGROUND: The potential effects of aerobic and resistance training in patients with severe chronic kidney disease (CKD) are not fully elucidated. This study investigated the effects of a home-based exercise programme on physical functioning and health-related quality of life (HRQOL) in patients with Stage 4 CKD, equivalent to estimated glomerular filtration rate of 15-30 mL/min/1.73 m2 . METHODS: Forty-six patients with Stage 4 CKD (median age, 73 years; 33 men) were randomly assigned to exercise (n = 23) and control (n = 23) groups. Exercise group patients performed aerobic exercise at 40-60% peak heart rate thrice weekly and resistance training at 70% of one-repetition maximum twice weekly at home for 6 months. Control patients received no specific intervention. Primary outcomes were distance in incremental shuttle walking test and HRQOL assessed using the Kidney Disease Quality of Life-Short Form questionnaire. Secondary outcomes included kidney function assessed with combined urea and creatinine clearance, urinary biomarkers, and anthropometric and biochemical parameters associated with CKD. RESULTS: Improvement in incremental shuttle walking test was significantly greater in the exercise group compared with controls (39.4 ± 54.6 vs. -21.3 ± 46.1; P < 0.001). Among Kidney Disease Quality of Life domains, significant mean differences were observed between the exercise group and the control group in work status, quality of social interaction, and kidney disease component summary outcomes (12.76 ± 5.76, P = 0.03; 5.97 ± 2.59, P = 0.03; and 4.81 ± 1.71, P = 0.007, respectively). There were greater reductions in natural log (ln)-transformed urinary excretion of liver-type fatty acid-binding protein, ln serum C-reactive protein, and acylcarnitine to free carnitine ratio in the exercise group compared with controls, with significant between-group differences of -0.579 ± 0.217 (P = 0.008), -1.13 ± 0.35 (P = 0.003), and -0. 058 ± 0.024 (P = 0.01), respectively. CONCLUSIONS: Our 6 month home-based exercise programme improved aerobic capacity and HRQOL in patients with Stage 4 CKD, with possible beneficial effects on kidney function and CKD-related parameters.
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Insuficiencia Renal Crónica , Entrenamiento de Fuerza , Anciano , Ejercicio Físico , Terapia por Ejercicio , Humanos , Masculino , Calidad de Vida , Insuficiencia Renal Crónica/terapiaRESUMEN
Diabetes and hypertension have become the primary causes of chronic kidney disease worldwide. However, there are no established markers for early diagnosis or predicting renal prognosis. Here, we investigated the expression profiles of DNA repair and DNA methylation factors in human urine-derived cells as a possible diagnostic or renal prognosis-predicting marker. A total of 75 subjects, aged 63.3 ± 1.9 years old, were included in this study. DNA and RNA were extracted from 50 mL of urine samples. We evaluated DNA double-strand breaks (DSBs) by the quantitative long distance-PCR method and performed real-time RT-PCR analysis to analyze the expression of renal cell-specific markers, DNA DSB repair factor KAT5, DNA methyltransferases DNMTs, and demethylation enzymes TETs. In patients with hypertension and diabetes, DNA DSBs of the nephrin gene increased with decreased urine KAT5/nephrin expression, consistent with our previous study (Cell Rep 2019). In patients with hypertension, DNA DSBs of the AQP1 gene were increased with elevated urine DNMTs/AQP1 and TETs/AQP1 expression. Moreover, urine DNMTs/AQP1 expression was significantly correlated with the annual eGFR decline rate after adjustment for age, baseline eGFR, the presence of diabetes and the amount of albuminuria, suggesting a possible role as a renal prognosis predictor.
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Roturas del ADN de Doble Cadena , Metilación de ADN , Diabetes Mellitus/patología , Hipertensión/patología , Orina/citología , Adulto , Anciano , Anciano de 80 o más Años , Acuaporina 1/genética , Acuaporina 1/metabolismo , ADN (Citosina-5-)-Metiltransferasas/genética , ADN (Citosina-5-)-Metiltransferasas/metabolismo , Femenino , Tasa de Filtración Glomerular , Humanos , Modelos Logísticos , Lisina Acetiltransferasa 5/genética , Lisina Acetiltransferasa 5/metabolismo , Masculino , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Persona de Mediana Edad , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/metabolismoRESUMEN
Accumulation of DNA double-strand breaks (DSBs) is linked to aging and age-related diseases. We recently reported the possible association of DNA DSBs with altered DNA methylation in murine models of kidney disease. However, DSBs and DNA methylation in human kidneys was not adequately investigated. This study was a cross-sectional observational study to evaluate the glomerular DNA DSB marker γH2AX and phosphorylated Ataxia Telangiectasia Mutated (pATM), and the DNA methylation marker 5-methyl cytosine (5mC) by immunostaining, and investigated the association with pathological features and clinical parameters in 29 patients with IgA nephropathy. To evaluate podocyte DSBs, quantitative long-distance PCR of the nephrin gene using laser-microdissected glomerular samples and immunofluorescent double-staining with WT1 and γH2AX were performed. Glomerular γH2AX level was associated with glomerular DNA methylation level in IgA nephropathy. Podocytopathic features were associated with increased number of WT1(+)γH2AX(+) cells and reduced amount of PCR product of the nephrin gene, which indicate podocyte DNA DSBs. Glomerular γH2AX and 5mC levels were significantly associated with the slope of eGFR decline over one year in IgA nephropathy patients using multiple regression analysis adjusted for age, baseline eGFR, amount of proteinuria at biopsy and immunosuppressive therapy after biopsy. Glomerular γH2AX level was associated with DNA methylation level, both of which may be a good predictor of renal outcome in IgA nephropathy.
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Daño del ADN , Metilación de ADN , Tasa de Filtración Glomerular , Glomerulonefritis por IGA/genética , Glomerulonefritis por IGA/fisiopatología , Glomérulos Renales/fisiopatología , Adulto , Femenino , Humanos , Glomérulos Renales/metabolismo , Masculino , Persona de Mediana EdadRESUMEN
Altered DNA methylation plays an important role in the onset and progression of kidney disease. However, little is known about how the changes arise in disease states. Here, we report that KAT5-mediated DNA damage repair is essential for the maintenance of kidney podocytes and is associated with DNA methylation status. Podocyte-specific KAT5-knockout mice develop severe albuminuria with increased DNA double-strand breaks (DSBs), increased DNA methylation of the nephrin promoter region, and decreased nephrin expression. Podocyte KAT5 expression is decreased, whereas DNA DSBs and DNA methylation are increased in diabetic nephropathy; moreover, KAT5 restoration by gene transfer attenuates albuminuria. Furthermore, KAT5 decreases DNA DSBs and DNA methylation at the same nephrin promoter region, which indicates that KAT5-mediated DNA repair may be related to DNA methylation status. These results suggest a concept in which an environment of DNA damage repair, which occurs with decreased KAT5, may affect DNA methylation status.