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Introduction: Endothelial cells have a crucial function in transporting and exchanging various nutrients. O-GlcNAcylation, mediated by O-GlcNAc transferase (OGT), involves the addition of N-acetylglucosamine to proteins and serves as an intracellular nutrient sensing mechanism. However, the role of O-GlcNAcylation in endothelial cells remains poorly understood. Objective: This study investigated the role of O-GlcNAcylation in endothelial cells. Methods: Endothelial-cell-specific Ogt -knockout mice (Ogt-ECKO) were generated by crossing Ogt-floxed mice (Ogt-flox) with VE-Cadherin Cre ERT2 mice. Ogt-ECKO mice and Ogt-flox control mice were subjected to a normal or high-fat diet, and their body weight, glucose metabolism, and lipid metabolism were examined. Results: Ogt-ECKO mice exhibited reduced body weight compared with Ogt-flox control mice under a high-fat diet. Lipid absorption was significantly impaired in Ogt-ECKO mice. Changes in the intercellular junctions of small intestinal lacteal endothelial cells from a button-like to a zipper-like configuration were observed. Furthermore, Ogt-ECKO mice showed decreased expression of VEGFR3. The administration of a nitric oxide donor restored lipid absorption and reversed the morphological alterations in Ogt-ECKO mice. Conclusions: These findings demonstrate the critical role of O-GlcNAcylation in endothelial cells in lipid absorption in the intestine through the modulation of lacteal junction morphology. These results provide novel insight into the metabolic regulatory mechanisms under physiological conditions and have implications for the development of new therapeutic strategies for obesity.
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OBJECTIVE: Carotid artery stenting (CAS) under flow reversal with dual protection using a proximal balloon and distal filter has been an established procedure for internal carotid artery (ICA) stenosis. This study investigates the effect of external carotid artery (ECA) occlusion on outcomes of CAS and ICA flow under flow reversal. METHODS: We reviewed 231 cases of CAS under flow reversal with ECA occlusion and 32 without. In the last 14 of 32 cases, the flow in the ICA under flow reversal was analyzed by ultrasound. The collateral index, which was defined as the total value of the maximum diameters of the ipsilateral anterior cerebral artery at the A1 segment and the anterior communicating artery, as well as those of the ipsilateral posterior cerebral artery at the P1 segment and the ipsilateral posterior communicating artery, and the maximum diameter of the ipsilateral ECA were correlated with the flow direction in the ICA. RESULTS: There was no significant difference in the outcome of CAS between the groups with or without ECA occlusion. Among the 14 cases without ECA occlusion, antegrade flow in the ICA was observed in 6 cases (42.9â¯%). The group with the antegrade flow in the ICA exhibited a significantly lower collateral index (5.08±0.33 vs 6.71±0.28, p=0.01) and a significantly larger ECA diameter (4.66±0.51â¯mm vs 3.21±1.24â¯mm, p=0.01) than the group with the stagnant or retrograde flow in the ICA. CONCLUSIONS: The outcomes of CAS under flow reversal were acceptable even without ECA occlusion. The ECA occlusion may not be necessary for CAS under dual protection; however, distal filter protection should be used even under flow reversal.
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Arteria Carótida Interna , Estenosis Carotídea , Stents , Humanos , Anciano , Masculino , Arteria Carótida Interna/diagnóstico por imagen , Arteria Carótida Interna/cirugía , Femenino , Estenosis Carotídea/cirugía , Estenosis Carotídea/diagnóstico por imagen , Estenosis Carotídea/fisiopatología , Persona de Mediana Edad , Resultado del Tratamiento , Anciano de 80 o más Años , Arteria Carótida Externa/diagnóstico por imagen , Circulación Cerebrovascular/fisiología , Estudios RetrospectivosRESUMEN
Acetate is a short-chain fatty acid (SCFA) that is produced by microbiota in the intestinal tract. It is an important nutrient for the intestinal epithelium, but also has a high plasma concentration and is used in the various tissues. Acetate is involved in endurance exercise, but its role in resistance exercise remains unclear. To investigate this, mice were administered either multiple antibiotics with and without oral acetate supplementation or fed a low-fiber diet. Antibiotic treatment for 2 weeks significantly reduced grip strength and the cross-sectional area (CSA) of muscle fiber compared with the control group. Intestinal concentrations of SCFAs were reduced in the antibiotic-treated group. Oral administration of acetate with antibiotics prevented antibiotic-induced weakness of skeletal muscle and reduced CSA of muscle fiber. Similarly, a low-fiber diet for 1 year significantly reduced the CSA of muscle fiber and fecal and plasma acetate concentrations. To investigate the role of acetate as an energy source, acetyl-CoA synthase 2 knockout mice were used. These mice had a shorter lifespan, reduced skeletal muscle mass and smaller CSA of muscle fiber than their wild type littermates. In conclusion, acetate derived from the intestinal microbiome can contribute to maintaining skeletal muscle performance.
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Acetatos , Microbioma Gastrointestinal , Ratones Endogámicos C57BL , Fuerza Muscular , Músculo Esquelético , Animales , Acetatos/farmacología , Acetatos/metabolismo , Músculo Esquelético/metabolismo , Músculo Esquelético/efectos de los fármacos , Ratones , Masculino , Fuerza Muscular/efectos de los fármacos , Microbioma Gastrointestinal/efectos de los fármacos , Microbioma Gastrointestinal/fisiología , Ratones Noqueados , Antibacterianos/farmacología , Ácidos Grasos Volátiles/metabolismo , Fibras de la Dieta/farmacología , Fibras de la Dieta/metabolismoAsunto(s)
Riñón , Transducción de Señal , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Humanos , Riñón/metabolismo , Riñón/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Animales , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Transportador 2 de Sodio-Glucosa/metabolismo , Nefropatías Diabéticas/metabolismo , Nefropatías Diabéticas/tratamiento farmacológico , Nefropatías Diabéticas/etiologíaRESUMEN
Dietary therapy is crucial for diabetes care with the aim of preventing the onset and progression of diabetes and its complications. The traditional approach to dietary therapy for diabetes has primarily focused on restricting the intake of the three major nutrients and rigorously controlling blood glucose levels. However, advancements in nutritional science have shown that within the three major nutrients - carbohydrates, proteins and lipids - there exist multiple types, each with distinct impacts on type 2 diabetes and its complications, sometimes even showing conflicting effects. In light of this, the present review shifts its focus from the quantity to the quality of the three major nutrients. It aims to provide an overview of how the differences in nutrient quality can influence onset and progression of type 2 diabetes and diabetic kidney disease, highlighting the diverse effects and, at times, contradictory impacts associated with each nutrient type.
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Diabetes Mellitus Tipo 2 , Nefropatías Diabéticas , Humanos , Nefropatías Diabéticas/dietoterapia , Nefropatías Diabéticas/prevención & control , Diabetes Mellitus Tipo 2/dietoterapia , Nutrientes/administración & dosificación , Valor Nutritivo , Carbohidratos de la Dieta/administración & dosificación , Proteínas en la Dieta/administración & dosificaciónRESUMEN
For the advancement of DKD treatment, identifying unrecognized residual risk factors is essential. We explored the impact of obesity diversity derived from different carbohydrate qualities, with an emphasis on the increasing trend of excessive fructose consumption and its effect on DKD progression. In this study, we utilized db/db mice to establish a novel diabetic model characterized by fructose overconsumption, aiming to uncover the underlying mechanisms of renal damage. Compared to the control diet group, the fructose-fed db/db mice exhibited more pronounced obesity yet demonstrated milder glucose intolerance. Plasma cystatin C levels were elevated in the fructose model compared to the control, and this elevation was accompanied by enhanced glomerular sclerosis, even though albuminuria levels and tubular lesions were comparable. Single-cell RNA sequencing of the whole kidney highlighted an increase in Lrg1 in glomerular endothelial cells (GECs) in the fructose model, which appeared to drive mesangial fibrosis through enhanced TGF-ß1 signaling. Our findings suggest that excessive fructose intake exacerbates diabetic kidney disease progression, mediated by aberrant Lrg1-driven crosstalk between GECs and mesangial cells.
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Nefropatías Diabéticas , Células Mesangiales , Ratones , Animales , Células Endoteliales/patología , Fructosa/efectos adversos , Nefropatías Diabéticas/patología , Ratones Endogámicos , Obesidad/complicaciones , Comunicación CelularRESUMEN
Ketone bodies have a negative image because of ketoacidosis, one of the acute and serious complications in diabetes. The negative image persists despite the fact that ketone bodies are physiologically produced in the liver and serve as an indispensable energy source in extrahepatic organs, particularly during long-term fasting. However, accumulating experimental evidence suggests that ketone bodies exert various health benefits. Particularly in the field of aging research, there is growing interest in the potential organoprotective effects of ketone bodies. In addition, ketone bodies have a potential role in preventing kidney diseases, including diabetic kidney disease (DKD), a diabetic complication caused by prolonged hyperglycemia that leads to a decline in kidney function. Ketone bodies may help alleviate the renal burden from hyperglycemia by being used as an alternative energy source in patients with diabetes. Furthermore, ketone body production may reduce inflammation and delay the progression of several kidney diseases in addition to DKD. Although there is still insufficient research on the use of ketone bodies as a treatment and their effects, their renoprotective effects are being gradually proven. This review outlines the ketone body-mediated renoprotective effects in DKD and other kidney diseases.
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Complicaciones de la Diabetes , Diabetes Mellitus , Nefropatías Diabéticas , Hiperglucemia , Cetosis , Humanos , Cuerpos Cetónicos/metabolismo , Cetosis/metabolismoRESUMEN
The prevalence of chronic kidney disease (CKD) is increasing worldwide, making the disease an urgent clinical challenge. Caloric restriction has various anti-aging and organ-protective effects, and unraveling its molecular mechanisms may provide insight into the pathophysiology of CKD. In response to changes in nutritional status, intracellular nutrient signaling pathways show adaptive changes. When nutrients are abundant, signals such as mechanistic target of rapamycin complex 1 (mTORC1) are activated, driving cell proliferation and other processes. Conversely, others, such as sirtuins and AMP-activated protein kinase, are activated during energy scarcity, in an attempt to compensate. Autophagy, a cellular self-maintenance mechanism that is regulated by such signals, has also been reported to contribute to the progression of various kidney diseases. Furthermore, in recent years, ketone bodies, which have long been considered to be detrimental, have been reported to play a role as starvation signals, and thereby to have renoprotective effects, via the inhibition of mTORC1. Therefore, in this review, we discuss the role of mTORC1, which is one of the most extensively studied nutrient-related signals associated with kidney diseases, autophagy, and ketone body metabolism; and kidney energy metabolism as a novel therapeutic target for CKD.
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Insuficiencia Renal Crónica , Transducción de Señal , Humanos , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina/farmacología , Transducción de Señal/fisiología , Proteínas Quinasas Activadas por AMP/metabolismo , Riñón/metabolismo , Autofagia , Insuficiencia Renal Crónica/tratamiento farmacológicoRESUMEN
The discovery of insulin approximately a century ago greatly improved the management of diabetes, including many of its life-threatening acute complications like ketoacidosis. This breakthrough saved many lives and extended the healthy lifespan of many patients with diabetes. However, there is still a negative perception of ketone bodies stemming from ketoacidosis. Originally, ketone bodies were thought of as a vital source of energy during fasting and exercise. Furthermore, in recent years, research on calorie restriction and its potential impact on extending healthy lifespans, as well as studies on ketone bodies, have gradually led to a reevaluation of the significance of ketone bodies in promoting longevity. Thus, in this review, we discuss the emerging and hidden roles of ketone bodies in various organs, including the heart, kidneys, skeletal muscles, and brain, as well as their potential impact on malignancies and lifespan.
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Diabetes Mellitus , Cetosis , Humanos , Cuerpos Cetónicos , Longevidad , CorazónRESUMEN
Renal artery stenosis-induced chronic renal ischemia is an important cause of renal dysfunction, especially in older adults, and its incidence is currently increasing. To elucidate the mechanisms underlying chronic renal hypoperfusion-induced kidney damage, we developed a novel mouse model of renal artery coiling-based chronic hypoperfusion-related kidney injury. This model exhibits decreased renal blood flow and function, atrophy, and parenchymal injury in the coiled kidney, along with compensatory hypertrophy in the non-coiled kidney, without chronic hypertension. The availability of this mouse model, which can develop renal ischemia without genetic modification, will enhance kidney disease research by serving as a new tool to investigate the effects of acquired factors (e.g., obesity and aging) and genetic factors on renal artery stenosis-related renal parenchymal damage.
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Transient neurological events (TNEs) occur after bypass surgery in Moyamoya disease (MMD); however, their pathology remains unknown. To elucidate the pathophysiology of TNEs, we investigated their relationship with perioperative superficial temporal artery (STA) blood flow volume, which was evaluated using ultrasonography. Forty-nine patients with MMD, who underwent direct bypass surgery, were included and stratified into TNE and non-TNE groups, respectively. The STA blood flow volume was evaluated at four time points (preoperatively and 2-4, 7, and 10-14 days postoperatively), and a change in volume during the postoperative period was defined as a flow volume mismatch. We investigated the association between ultrasonographic findings of flow volume mismatch and TNEs and magnetic resonance imaging findings, such as the cortical hyperintensity belt (CHB) sign, using univariate and path analyses. The STA blood flow volume increased immediately postoperatively, gradually decreasing over time, in both groups. The TNE group showed a significant increase in blood flow volume 2-4 days postoperatively (P = 0.042). Flow volume mismatch was significantly larger in the TNE group than in the non-TNE group (P = 0.020). In the path analysis, STA flow volume mismatch showed a positive association with the CHB sign (P = 0.023) and TNEs (P = 0.000). Additionally, the CHB sign partially mediated the association between STA flow volume mismatch and TNEs. These results suggest that significantly high STA blood flow volume changes occurring during the acute postoperative period after direct bypass surgery in MMD are correlated with TNEs and the CHB sign, suggesting involvement in the pathophysiology of TNEs.
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Revascularización Cerebral , Enfermedad de Moyamoya , Humanos , Enfermedad de Moyamoya/diagnóstico por imagen , Enfermedad de Moyamoya/cirugía , Complicaciones Posoperatorias , Imagen por Resonancia Magnética/métodos , Arterias Temporales/diagnóstico por imagen , Arterias Temporales/cirugía , Revascularización Cerebral/métodos , Arteria Cerebral Media/cirugíaRESUMEN
OBJECTIVE: Direct bypass surgery by superficial temporal artery (STA) - middle cerebral artery anastomosis is an established procedure for moyamoya disease (MMD). However, some patients may develop cerebral infarction (CI) due to the watershed shift phenomenon after the surgery. This study sought to investigate the correlation between the postoperative changes of STA flow as well as cerebral blood flow (CBF) and the incidence of CI after direct bypass surgery for MMD. METHODS: We conducted a retrospective study of 62 hemispheres in 50 subjects who underwent direct bypass surgery for MMD. All subjects underwent pre- and post-operative MR imaging, ultrasound evaluation of STA, and single-photon emission computed tomography. The presence of CI was correlated with preoperative CBF, the delta difference of each value of the STA between before and after the surgery, and the postoperative increase ratio of CBF. RESULTS: All bypass procedures were patent, and CI was observed in 4 cases (6.4%). There was no significant association between the incidence of CI and both pre- and post-operative CBF. However, there was a significant difference in delta pulsatility index (PI) of the STA between cases with or without CI (-0.38±0.22 and -0.87±0.63, respectively, p=0.03). Whereas, other factors did not show any significant differences between those with or without CI. CONCLUSIONS: A relatively high postoperative PI of the STA was significantly associated with the incidence of CI after direct bypass surgery for MMD. A larger study is needed to confirm these findings.
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Adipose tissues accumulate excess energy as fat and heavily influence metabolic homeostasis. O-linked N-acetylglucosamine (O-GlcNAc) modification (O-GlcNAcylation), which involves the addition of N-acetylglucosamine to proteins by O-GlcNAc transferase (Ogt), modulates multiple cellular processes. However, little is known about the role of O-GlcNAcylation in adipose tissues during body weight gain due to overnutrition. Here, we report on O-GlcNAcylation in mice with high-fat diet (HFD)-induced obesity. Mice with knockout of Ogt in adipose tissue achieved using adiponectin promoter-driven Cre recombinase (Ogt-FKO) gained less body weight than control mice under HFD. Surprisingly, Ogt-FKO mice exhibited glucose intolerance and insulin resistance, despite their reduced body weight gain, as well as decreased expression of de novo lipogenesis genes and increased expression of inflammatory genes, resulting in fibrosis at 24 weeks of age. Primary cultured adipocytes derived from Ogt-FKO mice showed decreased lipid accumulation. Both primary cultured adipocytes and 3T3-L1 adipocytes treated with OGT inhibitor showed increased secretion of free fatty acids. Medium derived from these adipocytes stimulated inflammatory genes in RAW 264.7 macrophages, suggesting that cell-to-cell communication via free fatty acids might be a cause of adipose inflammation in Ogt-FKO mice. In conclusion, O-GlcNAcylation is important for healthy adipose expansion in mice. Glucose flux into adipose tissues may be a signal to store excess energy as fat.NEW & NOTEWORTHY We evaluated the role of O-GlcNAcylation in adipose tissue in diet-induced obesity using adipose tissue-specific Ogt knockout mice. We found that O-GlcNAcylation in adipose tissue is essential for healthy fat expansion and that Ogt-FKO mice exhibit severe fibrosis upon long-term overnutrition. O-GlcNAcylation in adipose tissue may regulate de novo lipogenesis and free fatty acid efflux to the degree of overnutrition. We believe that these results provide new insights into adipose tissue physiology and obesity research.
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Acetilglucosamina , Ácidos Grasos no Esterificados , Animales , Ratones , Acetilglucosamina/metabolismo , Obesidad/genética , Obesidad/metabolismo , Tejido Adiposo/metabolismo , Peso Corporal/genética , Aumento de Peso , N-Acetilglucosaminiltransferasas/genética , N-Acetilglucosaminiltransferasas/metabolismoRESUMEN
Accumulating evidence suggests health benefits of ketone bodies, and especially for longevity. However, the precise role of endogenous ketogenesis in mammalian life span, and the safety and efficacy of the long-term exogenous supplementation of ketone bodies remain unclear. In the present study, we show that a deficiency in endogenous ketogenesis, induced by whole-body Hmgcs2 deletion, shortens life span in mice, and that this is prevented by daily ketone body supplementation using a diet containing 1,3-butanediol, a precursor of ß-hydroxybutyrate. Furthermore, feeding the 1,3-butanediol-containing diet from early in life increases midlife mortality in normal mice, but in aged mice it extends life span and prevents the high mortality associated with atherosclerosis in ApoE-deficient mice. By contrast, an ad libitum low-carbohydrate ketogenic diet markedly increases mortality. In conclusion, endogenous ketogenesis affects mammalian survival, and ketone body supplementation may represent a double-edged sword with respect to survival, depending on the method of administration and health status.
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Cuerpos Cetónicos , Longevidad , Ratones , Animales , Butileno Glicoles , Ácido 3-Hidroxibutírico , MamíferosRESUMEN
AIMS: This study aimed to evaluate changes in glycemic control and diabetes treatment by age group in Japanese patients with type 2 diabetes. METHODS: The study included the results of approximately 40,000 patients/year using cross-sectional and retrospective analyses from 2012 to 2019. RESULTS: There was little change in the glycemic control status in all age groups during the study period. However, by age group, patients aged ≤ 44 years continued to have the highest glycated hemoglobinA1c (HbA1c) values during the study period (7.4 % ± 1.7 % in 2012 and 7.4 % ± 1.5 % in 2019), especially in insulin-treated patients (8.3 % ± 1.9 % in 2012 and 8.4 % ± 1.8 % in 2019). Biguanides and dipeptidyl peptidase-4 inhibitors were widely prescribed. Sulfonylurea and insulin use showed a decreasing trend, but older patients had a higher percentage of prescriptions. Sodium glucose transporter 2 inhibitors were prescribed rapidly, especially in younger patients. CONCLUSIONS: There were no obvious changes in glycemic control over time in the study period. The mean HbA1c level was higher in younger patients, which suggested that improvement is required. In older patients, there was a trend toward greater emphasis on management to avoid hypoglycemia. Different treatment strategies based on age showed different drug choices.
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Diabetes Mellitus Tipo 2 , Control Glucémico , Hipoglucemiantes , Pautas de la Práctica en Medicina , Anciano , Humanos , Glucemia/análisis , Estudios Transversales , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/epidemiología , Diabetes Mellitus Tipo 2/etnología , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Pueblos del Este de Asia/estadística & datos numéricos , Hemoglobina Glucada/análisis , Control Glucémico/tendencias , Hipoglucemiantes/uso terapéutico , Insulina/uso terapéutico , Estudios Retrospectivos , Pautas de la Práctica en Medicina/tendencias , Factores de EdadRESUMEN
OBJECTIVE: Intraoperative spinal angiography via the popliteal artery for patients in the prone position has been reported only twice in 4 patients. This study aimed to clarify the safety precautions to be taken with this technique in a larger patient cohort. METHODS: Seven patients with spinal vascular disorders underwent intraoperative spinal angiography in the prone position via the popliteal artery. Ultrasound was used to evaluate the neurovascular anatomy in the popliteal fossa and guide the arterial puncture. Patient characteristics, features of angiography devices, puncture attempts, and angiography-related complications, such as hematoma formation and injury to the neurovascular bundle, were analyzed. RESULTS: The average number of arterial puncture attempts was 1.3 times (range: 1-2). Sheaths (4 and 4.5 Fr) with different ineffective lengths were used. In 1 case, a 4.5-Fr sheath was replaced with a 4-Fr sheath with a shorter noneffective length as the length of the catheter limited access to the target. Catheters with Type-JB2 tip shapes were used for craniocervical junction lesions, and those with Type-KAGAWA tip shapes were used for thoracic and lumbar spinal lesions. No puncture site complications were observed in any patient. CONCLUSIONS: Intraoperative spinal angiography via the popliteal artery was an effective tool in surgeries for spinal vascular diseases. The introduction of the ultrasound enabled atraumatic puncture of the popliteal artery. Spinal targets above T5 to T6 may be inaccessible from the popliteal fossa when using a 100-cm-long catheter.
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Malformaciones Arteriovenosas , Enfermedades del Sistema Nervioso , Enfermedades Vasculares , Humanos , Arteria Poplítea/diagnóstico por imagen , Arteria Poplítea/cirugía , Punción Espinal , Angiografía , Malformaciones Arteriovenosas/cirugíaRESUMEN
This study, which included serological and cellular immunity tests, evaluated whether coronavirus disease 2019 (COVID-19) vaccination adequately protected healthcare workers (HCWs) from COVID-19. Serological investigations were conducted among 1600 HCWs (mean ± standard deviation, 7.4 ± 1.4 months after the last COVID-19 vaccination). Anti-SARS-CoV-2 antibodies N-Ig, Spike-Ig (Roche), N-IgG, Spike-IgM, and -IgG (Abbott), were evaluated using a questionnaire of health condition. 161 HCWs were analyzed for cellular immunity using T-SPOT® SARS-CoV-2 kit before, and 52 HCWs were followed up until 138.3 ± 15.7 days after their third vaccination. Spike-IgG value was 954.4 ± 2282.6 AU/mL. Forty-nine of the 1600 HCWs (3.06%) had pre-existing SARS-CoV-2 infection. None of the infectious seropositive HCWs required hospitalization. T-SPOT value was 85.0 ± 84.2 SFU/106 cells before the third vaccination, which increased to 219.4 ± 230.4 SFU/106 cells immediately after, but attenuated later (to 111.1 ± 133.6 SFU/106 cells). Poor counts (< 40 SFU/106 cells) were present in 34.8% and 38.5% of HCWs before and after the third vaccination, respectively. Our findings provide insights into humoral and cellular immune responses to repeated COVID-19 vaccinations. COVID-19 vaccination was effective in protecting HCWs from serious illness during the original Wuhan-1, Alpha, Delta and also ongoing Omicron-predominance periods. However, repeated vaccinations using current vaccine versions may not induce sufficient cellular immunity in all HCWs.
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COVID-19 , Humanos , COVID-19/epidemiología , COVID-19/prevención & control , SARS-CoV-2 , Vacunas contra la COVID-19 , Japón/epidemiología , Personal de Salud , Vacunación , Inmunoglobulina G , Inmunoglobulina MRESUMEN
Objective Evaluating the rate of decline in the estimated glomerular filtration rate (eGFR) may help identify patients with occult chronic kidney disease (CKD). We herein report that eGFR fluctuation complicates the assessment of the rate of decline and propose a long-term eGFR plot analysis as a solution. Methods In 142 patients with persistent eGFR decline in a single hospital, we evaluated the factors influencing the rate of eGFR decline, calculated over the long term (≥3 years) and short term (<3 years) using eGFR plots, taking into account eGFR fluctuation between visits. Results The difference between the rate of eGFR decline calculated using short- and long-term plots increased as the time period considered in the short-term plots became shorter. A regression analysis revealed that eGFR fluctuation was the only factor that explained the difference and that the fluctuation exceeded the annual eGFR decline in all participants. Furthermore, the larger the eGFR fluctuation, the more difficult it became to detect eGFR decline using a short-term eGFR analysis. Obesity, a high eGFR at baseline, and faster eGFR decline were associated with larger eGFR fluctuations. To circumvent the issue of eGFR fluctuation in the assessment of the rate of eGFR decline, we developed a system that generates a long-term eGFR plot using all eGFR values for a participant, which enabled the detection of occult CKD, facilitating early therapeutic intervention. Conclusion The construction of long-term eGFR plots is useful for identifying patients with progressive eGFR decline, as it minimizes the effect of eGFR fluctuation.
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Insuficiencia Renal Crónica , Tasa de Filtración Glomerular , Humanos , Riñón/fisiología , Obesidad , Análisis de Regresión , Factores de RiesgoRESUMEN
Lipoprotein lipase (LPL) is an enzyme that catalyzes the hydrolysis of circulating triglyceride and the transport of fatty acids into cells. Its activity is positively regulated by insulin, and insulin resistance is associated with low LPL activity and subsequent hypertriglyceridemia. The involvement of hypertriglyceridemia in chronic kidney disease (CKD) is still under the debate in a clinical setting. Therefore, we aimed to study the role of hypertriglyceridemia in the disease using mice with systemic or renal-specific LPL deficiency. Systemic LPL deficiency was characterized by hypertriglyceridemia, but not renal injury or dyslipidemia-related conditions, such as fatty liver. Furthermore, the LPL deficiency-induced hypertriglyceridemia was not associated with a worsening of the CKD phenotype or atherosclerosis, even when CKD was induced by 5/6 nephrectomy. Next, because LPL-mediated fatty acid uptake may be important for energy metabolism in proximal tubular epithelial cells (PTECs), the role of renal LPL in renal physiology was studied by generating mice lacking LPL specifically in PTECs. These mice showed no abnormalities in their histology or renal reabsorption of micro molecules. These findings suggest that systemic and renal lipid abnormalities caused by LPL deficiency do not cause or worsen the development of renal injury, and provide novel insight regarding the potential role of lipotoxicity in the pathogenesis of obesity-related kidney injury.
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Hiperlipoproteinemia Tipo I , Hipertrigliceridemia , Insuficiencia Renal Crónica , Animales , Riñón/metabolismo , Lipoproteína Lipasa/metabolismo , Ratones , Insuficiencia Renal Crónica/etiología , Triglicéridos/metabolismoRESUMEN
Ketone bodies, including 3HBA, are endogenous products of fatty acid oxidation, and Hmgcs2 is the first rate-limiting enzyme of ketogenesis. From database analysis and in vivo and in vitro experiments, we found that adipose tissue and adipocytes express Hmgcs2, and that adipocytes produce and secrete 3HBA. Treatment with 3HBA enhanced the gene expression levels of the antioxidative stress factors, PPARγ, and lipogenic factors in adipose tissue in vivo and in adipocytes in vitro, accompanied by reduced ROS levels. Knockdown of endogenous Hmgcs2 in adipocytes markedly decreased 3HBA levels in adipocytes and decreased the gene expression levels of the antioxidative stress factors, PPARγ, and lipogenic factors with increased ROS levels. Conversely, overexpression of Hmgcs2 in adipocytes increased 3HBA secretion from adipocytes and enhanced the gene expression levels of the antioxidative stress factors, PPARγ, and lipogenic factors. These results demonstrate that 3HBA plays significant roles in enhancing the physiological function of adipocytes.