RESUMO
Roles of the renin-angiotensin system in autophagy and ischemia/reperfusion (I/R) injury in the kidney have not been fully characterized. Here we examined the hypothesis that modest activation of the angiotensin II (Ang II) receptor upregulates autophagy and increases renal tolerance to I/R injury. Sprague-Dawley rats were assigned to treatment with a vehicle or a non-pressor dose of Ang II (200 ng/kg/min) for 72 h before 30-min renal I/R. LC3-immunohistochemistry showed that Ang II treatment increased autophagosomes in proximal tubular cells by 2.7 fold. In Ang II-pretreated rats, autophagosomes were increased by 2.5 fold compared to those in vehicle-treated rats at 4 h after I/R, when phosphorylation of Akt and S6 was suppressed and ULK1-Ser555 phosphorylation was increased. Serum creatinine and urea nitrogen levels, incidence of oliguria, and histological score of tubular necrosis at 24 h after I/R were attenuated by Ang II-pretreatment. In NRK-52E cells, Ang II induced LC3-II upregulation, which was inhibited by losartan but not by A779. The results indicate that a non-pressor dose of Ang-II promotes autophagy via ULK1-mediated signaling in renal tubular cells and attenuates renal I/R injury. The AT1 receptor, but not the Mas receptor, contributes to Ang-II-induced autophagy and presumably also to the renoprotection.
Assuntos
Angiotensina II/administração & dosagem , Angiotensina II/farmacologia , Autofagia/efeitos dos fármacos , Túbulos Renais Proximais/citologia , Receptores de Angiotensina/metabolismo , Receptores de Angiotensina/fisiologia , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/prevenção & controle , Animais , Autofagia/genética , Células Cultivadas , Masculino , Ratos Sprague-Dawley , Sistema Renina-Angiotensina/fisiologia , Traumatismo por Reperfusão/etiologiaRESUMO
BACKGROUND: The risk of contrast-induced nephropathy (CIN) is high in patients with chronic kidney disease (CKD). However, the mechanism of CIN in CKD is not fully understood. Here, we prepared a clinically relevant model of CIN and examined the role of necroptosis, which potentially cross-talks with autophagy, in CIN. METHODS: In Sprague-Dawley rats, CKD was induced by subtotal nephrectomy (SNx, 5/6 nephrectomy) 4 weeks before induction of CIN. CIN was induced by administration of a contrast medium (CM), iohexol, following administration of indomethacin and N-omega-Nitro-L-arginine methyl ester. Renal function and tissue injuries were assessed 48 h after CM injection. RESULTS: Serum creatinine (s-Cre) and BUN were increased from 0.28 ± 0.01 to 0.52 ± 0.02 mg/dl and from 15.1 ± 0.7 to 29.2 ± 1.2 mg/dl, respectively, after SNx alone. CM further increased s-Cre and BUN to 0.69 ± 0.03 and 37.2 ± 2.1, respectively. In the renal tissue after CM injection, protein levels of receptor-interacting serine/threonine-protein kinase (RIP) 1, RIP3, cleaved caspase 3, and caspase 8 were increased by 64 ~ 212%, while there was reduction in LC3-II and accumulation of p62. Necrostatin-1, an RIP1 inhibitor, administered before and 24 h after CM injection significantly suppressed elevation of s-Cre, BUN and urinary albumin levels, kidney injury molecule-1 expression and infiltration of CD68-positive macrophages in renal tissues after CM injection. CONCLUSION: The results suggest that necroptosis of proximal tubular cells contributes to CIN in CKD and that suppression of protective autophagy by pro-necroptotic signaling may also be involved.
Assuntos
Injúria Renal Aguda/induzido quimicamente , Meios de Contraste/efeitos adversos , Iohexol/efeitos adversos , Necroptose , Insuficiência Renal Crônica/complicações , Injúria Renal Aguda/patologia , Animais , Modelos Animais de Doenças , Túbulos Renais Proximais/ultraestrutura , Masculino , Ratos Sprague-DawleyRESUMO
BACKGROUND: Atrial fibrillation (AF) is an established risk factor for ischemic stroke in a general population. However, its impact in patients on hemodialysis (HD), a group with a high risk for stroke, is still controversial. Here we examined this issue in a Japanese cohort. METHODS: This study was designed as a multicenter cohort study. HD patients (n = 1,067) were enrolled from 22 institutes in January 2009 and followed up for 3 years. Patients with missing data (n = 196) or kidney transplantation (n = 4) were excluded, and 867 patients contributed to the analysis of the risk of new-onset of ischemic stroke. RESULTS: At baseline, AF was observed in 123 patients (14.2%, AF group) and not in the others (n = 744: 85.8%, non-AF group). During a follow-up period of 31.3 months, the cumulative incidence rate for ischemic stroke was significantly higher in the AF group than in the non-AF group (6.5% vs. 2.9%, p < 0.05). In Cox regression analysis, AF was a significant independent risk factor for new-onset of ischemic stroke after adjustment for age, sex, prior history of ischemic stroke, use of warfarin, dialysis vintage, comorbidity of diabetic nephropathy, and interdialytic weight gain (hazard ratio 2.17-2.68). CONCLUSION: Present analyses using comprehensive adjustment for multiple confounders, including prior history of ischemic stroke, indicated that AF independently increases the risk of new-onset of ischemic stroke by more than twofold in Japanese HD patients.
Assuntos
Fibrilação Atrial/epidemiologia , AVC Isquêmico/epidemiologia , Nefropatias/terapia , Diálise Renal/efeitos adversos , Idoso , Fibrilação Atrial/diagnóstico , Feminino , Humanos , Incidência , AVC Isquêmico/diagnóstico , Japão/epidemiologia , Nefropatias/diagnóstico , Nefropatias/epidemiologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do TratamentoRESUMO
Cadmium (Cd) is a toxic heavy metal that is mainly accumulated through the consumption of foods produced in Cd-contaminated fields. Phytoremediation is one of the most effective methods to reduce the soil Cd concentration. In this study, we bred a new rice line, 'Akita 119', for Cd phytoremediation. 'Akita 119' was obtained by a soft X-ray mutation of 'Cho-ko-koku', a naturally high-Cd-accumulating rice cultivar. The heading date of 'Akita 119' was about 2 weeks later than that of 'Akitakomachi', which is the leading cultivar in Akita Prefecture, Japan. 'Akita 119' has a short culm length and many panicles. The shattering resistance and lodging resistance of 'Akita 119' were improved compared to 'Cho-ko-koku'. The thousand-grain weight of 'Akita 119' was much smaller than that of 'Akitakomachi', and grains of 'Akita 119' could be easily distinguished from general japonica cultivars. When 'Akita 119' was grown in Cd-contaminated fields, the shoot dry weight and Cd concentration were similar to those of 'Cho-ko-koku'. These results demonstrate that 'Akita 119' has improved agronomic characteristics compared to 'Cho-ko-koku' while retaining the ability to extract Cd. Therefore, it should be considered a promising candidate for Cd phytoremediation in paddy fields in northern parts of Japan.
RESUMO
Objective: In this study, we investigated whether the COVID-19 pandemic affected achievement of guideline targets for HbA1c, blood pressure (BP), and low-density lipoprotein (LDL) cholesterol in people with diabetes mellitus (DM). Materials and methods: Data for 556 people with DM who were treated regularly for 4 years before and during the COVID-19 pandemic in Japan were analyzed in this retrospective study. Achieved targets were defined as HbA1c < 7.0%, BP < 130/80 mmHg, and LDL cholesterol < 100 or < 120 mg/dL depending on the presence or absence of coronary artery disease. Results: In 2019, before the start of the COVID-19 pandemic, achievement rates of guideline targets for HbA1c, BP and LDL cholesterol were 53.4%, 45.9% and 75.7%, respectively. In 2020, the achievement rates for HbA1c and BP targets were significantly decreased to 40.8% and 31.3%, respectively. The achievement rates for the HbA1c target gradually recovered to 49.3% in 2021 and to 51.1% in 2022. However, recovery in achieving the BP target was slow, remaining at 40.5% even in 2022. On the other hand, the achievement rate for the LDL cholesterol target was not affected and remained relatively high during the COVID-19 pandemic. Conclusions: The rates of achieving therapeutic targets for HbA1c and BP have not been high enough in people with DM, and the rates were further reduced by lifestyle changes due to the COVID-19 pandemic. Although there has been a trend toward improvement with the lifting of behavioral restrictions, more intensified treatment is necessary to achieve good control. Supplementary Information: The online version contains supplementary material available at 10.1007/s13340-024-00715-8.
RESUMO
Background: Post hoc analysis of the PARADIGM-HF trial showed that sacubitril/valsartan (S/V) was more effective than enalapril in lowering HbA1c in patients with heart failure and diabetes. MethodsâandâResults: In the present study, the effect of S/V on glycemic control was retrospectively analyzed in 150 patients (median age 74 years) who were prescribed S/V for the treatment of heart failure and/or hypertension. After a median period of 13 weeks treatment, mean (±SD) HbA1c levels decreased significantly from 6.56±0.68% to 6.49±0.63%. The decrease in HbA1c was evident in patients with (n=111), but not in those without, diabetes. There were no significant changes in renal function after S/V treatment, but systolic blood pressure was significantly reduced from 141±21 to 134±19 mmHg. Ninety patients had N-terminal pro B-type natriuretic peptide (NT-proBNP) tested, and S/V significantly decreased median NT-proBNP concentrations from 1,026 to 618 pg/mL; however, there was no correlation between the degree of decrease in HbA1c and that in NT-proBNP. Multiple regression analysis revealed that being diabetic, rather than having heart failure, was a significant independent variable for a reduction in HbA1c. Conclusions: Treatment with S/V improved glycemic control in patients with heart failure and/or hypertension, especially in those with concomitant diabetes. This favorable effect on glucose metabolism may be mediated by neprilysin inhibition and is desirable in the treatment of heart failure and hypertension in diabetic patients.
RESUMO
Accumulating evidence indicates that necroptosis contributes to cardiovascular diseases. We recently reported suppression of autophagy by necroptotic signals in cardiomyocytes and protective action of rapamycin. Here we examined the mechanism by which mTORC1 inhibition protects cardiomyocytes from necroptosis. Necroptosis of H9c2 cells was induced by treatment with tumor necrotic factor-α (TNF) and z-VAD-fmk (zVAD), and the extent of necroptosis was determined as the level of LDH release (as % of total). TNF/zVAD increased RIP1-RIP3 interaction and LDH release from 3.4⯱â¯1.3% to 46.1⯱â¯2.3%. The effects of TNF/zVAD were suppressed by an mTORC1 inhibitor, rapamycin, and an mTORC1/2 inhibitor, Ku-0063794, but not by a p70s6K inhibitor, PF-4708671. Protection by rapamycin was not abolished by inhibitors of TAK1, IKKα/ß, and cIAP, endogenous necroptosis suppressors upstream of RIP1. Rapamycin and Ku-0063794 suppressed TNF/zVAD-induced RIP1-Ser166 phosphorylation and increased phosphorylation of RIP1-Ser320, an inhibitory phosphorylation site, though such an effect on RIP1-Ser320 was not observed for PF-4708671. Protective effects of rapamycin on TNF/zVAD-induced RIP1-RIP3 binding and necroptosis were undetected in cells transfected with RIP1-S320A. In TNF/zVAD-treated cells, rapamycin and a RIP1 inhibitor, necrostatin-1, increased nuclear localization of transcriptional factor EB (TFEB) and promoted autolysosome formation from autophagosomes in a TFEB-dependent manner. Knockdown of TFEB expression attenuated rapamycin-induced protection from necroptosis in TNF/zVAD-treated cells. The results suggest that mTORC1 inhibition promotes autophagy and protects cardiomyocytes from necroptosis by a TFEB-dependent mechanism and that inhibition of RIP1 by increased phosphorylation at Ser320 is crucial in the cardiomyocyte protection afforded by mTORC1 inhibition.
Assuntos
Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/antagonistas & inibidores , Necroptose/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/metabolismo , Sirolimo/farmacologia , Animais , Autofagia/efeitos dos fármacos , Cardiotônicos/farmacologia , Linhagem Celular , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Miócitos Cardíacos/citologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Ratos , Proteína Serina-Treonina Quinases de Interação com ReceptoresRESUMO
AIMS/INTRODUCTION: Type 2 diabetes mellitus is a risk factor of acute kidney injury after myocardial infarction (MI), a form of cardiorenal syndrome. Recent clinical trials have shown that a sodium-glucose cotransporter 2 (SGLT2) inhibitor improved both cardiac and renal outcomes in patients with type 2 diabetes mellitus, but effects of an SGLT2 inhibitor on cardiorenal syndrome remain unclear. MATERIALS AND METHODS: Type 2 diabetes mellitus (Otsuka Long-Evans Tokushima Fatty rats [OLETF]) and control (Long-Evans Tokushima Otsuka rats [LETO]) were treated with canagliflozin, an SGLT2 inhibitor, for 2 weeks. Renal tissues were analyzed at 12 h after MI with or without preoperative fasting. RESULTS: Canagliflozin reduced blood glucose levels in OLETF, and blood ß-hydroxybutyrate levels were increased by canagliflozin only with fasting. MI increased neutrophil gelatinase-associated lipocalin and kidney injury molecule-1 protein levels in the kidney by 3.2- and 1.6-fold, respectively, in OLETF, but not in LETO. The renal messenger ribonucleic acid level of Toll-like receptor 4 was higher in OLETF than in LETO after MI, whereas messenger ribonucleic acid levels of cytokines/chemokines were not significantly different. Levels of lipid peroxides, nicotinamide adenine dinucleotide phosphate oxidase (NOX)2 and NOX4 proteins after MI were significantly higher in OLETF than in LETO. Canagliflozin with pre-MI fasting suppressed MI-induced renal expression of neutrophil gelatinase-associated lipocalin and kidney injury molecule-1 in OLETF, together with reductions in lipid peroxides and NOX proteins in the kidney. Blood ß-hydroxybutyrate levels before MI were inversely correlated with neutrophil gelatinase-associated lipocalin protein levels in OLETF. Pre-incubation with ß-hydroxybutyrate attenuated angiotensin II-induced upregulation of NOX4 in NRK-52E cells. CONCLUSIONS: The findings suggest that SGLT2 inhibitor treatment with a fasting period protects kidneys from MI-induced cardiorenal syndrome, possibly by ß-hydroxybutyrate-mediated reduction of NOXs and oxidative stress, in type 2 diabetic rats.
Assuntos
Injúria Renal Aguda/prevenção & controle , Canagliflozina/farmacologia , Síndrome Cardiorrenal/prevenção & controle , Diabetes Mellitus Tipo 2/complicações , Infarto do Miocárdio/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Injúria Renal Aguda/etiologia , Animais , Síndrome Cardiorrenal/etiologia , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Infarto do Miocárdio/etiologia , Ratos , Ratos Endogâmicos OLETFRESUMO
Diabetes mellitus is a major risk factor for acute kidney injury (AKI). Here, we hypothesized that suppression of autophagic response underlies aggravation of renal ischemia/reperfusion (I/R) injury by type 2 diabetes mellitus (T2DM). In OLETF, a rat model of T2DM, and its non-diabetic control, LETO, AKI was induced by unilateral nephrectomy and 30-min occlusion and 24-h reperfusion of the renal artery in the contralateral kidney. Levels of serum creatinine and blood urea nitrogen and tubular injury score after I/R were significantly higher in OLETF than in LETO. Administration of chloroquine, a widely used autophagy inhibitor, aggravated I/R-induced renal injury in LETO, but not in OLETF. In contrast to LETO, OLETF exhibited no increase in autophagosomes in the proximal tubules after I/R. Immunoblotting showed that I/R activated the AMPK/ULK1 pathway in LETO but not in OLETF, and mTORC1 activation after I/R was enhanced in OLETF. Treatment of OLETF with rapamycin, an mTORC1 inhibitor, partially restored autophagic activation in response to I/R and significantly attenuated I/R-induced renal injury. Collectively, these findings indicate that suppressed autophagic activation in proximal tubules by impaired AMPK/ULK1 signaling and upregulated mTORC1 activation underlies T2DM-induced worsening of renal I/R injury.
Assuntos
Autofagia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/patologia , Nefropatias/fisiopatologia , Traumatismo por Reperfusão/fisiopatologia , Animais , Nitrogênio da Ureia Sanguínea , Creatinina/sangue , Modelos Animais de Doenças , Nefropatias/patologia , Túbulos Renais Proximais/patologia , Alvo Mecanístico do Complexo 1 de Rapamicina/análise , Ratos , Traumatismo por Reperfusão/patologiaRESUMO
BACKGROUND: Angiotensin-converting enzyme 2 (ACE2) is highly expressed in the kidney and converts angiotensin (Ang) II to Ang-(1-7), a renoprotective peptide. Urinary ACE2 has been shown to be elevated in patients with chronic kidney disease. However, the effects of antihypertensive agents on urinary ACE2 remain unclear. METHODS: Of participants in the Tanno-Sobetsu cohort study in 2011 (n = 617), subjects on no medication (n = 101) and hypertensive patients treated with antihypertensive agents, including the calcium channel blockers amlodipine and long-acting nifedipine; the ACE inhibitor enalapril; and the Ang II receptor blockers losartan, candesartan, valsartan, telmisartan, and olmesartan, for more than 1 year (n = 100) were enrolled, and urinary ACE2 level was measured. RESULTS: Glucose and hemoglobin A1c were significantly higher in patients treated with enalapril, telmisartan or olmesartan than in the control subjects. Urinary albumin-to-creatinine ratio (UACR) was significantly higher in patients treated with enalapril than in the control subjects. Urinary ACE2 level was higher in the olmesartan-treated group, but not the other treatment groups, than in the control group. Urinary ACE2 level was positively correlated with systolic blood pressure (r = 0.211; P = 0.003), UACR (r = 0.367; P < 0.001), and estimated salt intake (r = 0.260; P < 0.001). Multivariable regression analysis after adjustment of age, sex, and the correlated indices showed that the use of olmesartan was an independent predictor of urinary ACE2 level. CONCLUSIONS: In contrast with other antihypertensive drugs, olmesartan may uniquely increase urinary ACE2 level, which could potentially offer additional renoprotective effects.