RESUMO
The mechanisms responsible for glomerular hemodynamic regulation with sodium-glucose co-transporter 2 (SGLT2) inhibitors in kidney disease due to type 2 diabetes remain unclear. Therefore, we investigated changes in glomerular hemodynamic function using an animal model of type 2 diabetes, treated with an SGLT2 inhibitor alone or in combination with a renin-angiotensin-aldosterone system inhibitor using male Zucker lean (ZL) and Zucker diabetic fatty (ZDF) rats. Afferent and efferent arteriolar diameter and single-nephron glomerular filtration rate (SNGFR) were evaluated in ZDF rats measured at 0, 30, 60, 90, and 120 minutes after the administration of a SGLT2 inhibitor (luseogliflozin). Additionally, we assessed these changes under the administration of the adenosine A1 receptor (A1aR) antagonist (8-cyclopentyl-1,3-dipropylxanthine), along with coadministration of luseogliflozin and an angiotensin II receptor blocker (ARB), telmisartan. ZDF rats had significantly increased SNGFR, and afferent and efferent arteriolar diameters compared to ZL rats, indicating glomerular hyperfiltration. Administration of luseogliflozin significantly reduced afferent vasodilatation and glomerular hyperfiltration, with no impact on efferent arteriolar diameter. Urinary adenosine levels were increased significantly in the SGLT2 inhibitor group compared to the vehicle group. A1aR antagonism blocked the effect of luseogliflozin on kidney function. Co-administration of the SGLT2 inhibitor and ARB decreased the abnormal expansion of glomerular afferent arterioles, whereas the efferent arteriolar diameter was not affected. Thus, regulation of afferent arteriolar vascular tone via the A1aR pathway is associated with glomerular hyperfiltration in type 2 diabetic kidney disease.
Assuntos
Diabetes Mellitus Tipo 2 , Nefropatias Diabéticas , Taxa de Filtração Glomerular , Glomérulos Renais , Inibidores do Transportador 2 de Sódio-Glicose , Animais , Masculino , Ratos , Antagonistas do Receptor A1 de Adenosina/farmacologia , Arteríolas/efeitos dos fármacos , Arteríolas/fisiopatologia , Diabetes Mellitus Experimental/fisiopatologia , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/fisiopatologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/fisiopatologia , Taxa de Filtração Glomerular/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Glomérulos Renais/efeitos dos fármacos , Glomérulos Renais/fisiopatologia , Glomérulos Renais/patologia , Glomérulos Renais/irrigação sanguínea , Ratos Zucker , Sistema Renina-Angiotensina/efeitos dos fármacos , Transportador 2 de Glucose-Sódio/metabolismo , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Sorbitol/análogos & derivados , Xantinas/farmacologiaRESUMO
There are cases in which CKD progression is difficult to evaluate, because the changes in estimated glomerular filtration rate (eGFR) and proteinuria sometimes show opposite directions as CKD progresses. Indices and models that enable the easy and accurate risk prediction of end-stage-kidney disease (ESKD) are indispensable to CKD therapy. In this study, we investigated whether a CKD stage coordinate transformed into a vector field (CKD potential model) accurately predicts ESKD risk. Meta-analysis of large-scale cohort studies of CKD patients in PubMed was conducted to develop the model. The distance from CKD stage G2 A1 to a patient's data on eGFR and proteinuria was defined as r. We developed the CKD potential model on the basis of the data from the meta-analysis of three previous cohort studies: ESKD risk = exp(r). Then, the model was validated using data from a cohort study of CKD patients in Japan followed up for three years (n = 1,564). Moreover, the directional derivative of the model was developed as an index of CKD progression velocity. For ESKD prediction in three years, areas under the receiver operating characteristic curves (AUCs) were adjusted for baseline characteristics. Cox proportional hazards models with spline terms showed the exponential association between r and ESKD risk (p<0.0001). The CKD potential model more accurately predicted ESKD with an adjusted AUC of 0.81 (95% CI 0.76, 0.87) than eGFR (p<0.0001). Moreover, the directional derivative of the model showed a larger adjusted AUC for the prediction of ESKD than the percent eGFR change and eGFR slope (p<0.0001). Then, a chart of the transformed CKD stage was developed for implementation in clinical settings. This study indicated that the transformed CKD stage as a vector field enables the easy and accurate estimation of ESKD risk and CKD progression and suggested that vector analysis is a useful tool for clinical studies of CKD and its related diseases.
Assuntos
Falência Renal Crônica , Insuficiência Renal Crônica , Humanos , Estudos de Coortes , Progressão da Doença , Insuficiência Renal Crônica/complicações , Falência Renal Crônica/terapia , Falência Renal Crônica/complicações , Proteinúria/complicações , Taxa de Filtração GlomerularRESUMO
BACKGROUND: It is well known that kidney injury is vital organ damage in Fabry disease (FD). Renin-angiotensin system (RAS) inhibitors are known to reduce proteinuria in patients with chronic kidney disease (CKD) by dilating the glomerular export arteries and reducing intraglomerular pressure. This improvement in intraglomerular pressure, although lowering the glomerular filtration rate, is thought to prevent renal damage and be renoprotective in the long term. RAS inhibitors may be effective in FD patients with proteinuria to prevent the progression of kidney disease, however, the degree to which they are used in clinical practice is unknown. METHODS: The J-CKD-DB-Ex is a comprehensive multicenter database that automatically extracts medical data on CKD patients. J-CKD-DB-Ex contains data on 187,398 patients in five medical centers. FD patients were identified by ICD-10. Clinical data and prescriptions of FD patients between January 1 of 2014, and December 31 of 2020 were used for the analysis. RESULTS: We identified 39 patients with FD from the J-CKD-DB-Ex including those with suspected FD. We confirmed 22 patients as FD. Half of the patients received RAS inhibitors. RAS inhibitors tended to be used in CKD patients with more severe renal impairment. CONCLUSIONS: This case series revealed the actual clinical practice of FD patients with CKD. In particular, we found cases in which patients had proteinuria, but were not treated with RAS inhibitors. The database was shown to be useful in assessing the clinical patterns of patients with rare diseases.
Assuntos
Doença de Fabry , Insuficiência Renal Crônica , Doença de Fabry/complicações , Doença de Fabry/tratamento farmacológico , Humanos , Masculino , Feminino , Insuficiência Renal Crônica/fisiopatologia , Japão/epidemiologia , Pessoa de Meia-Idade , Adulto , Proteinúria/tratamento farmacológico , Proteinúria/etiologia , Adulto Jovem , Bases de Dados Factuais , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Idoso , Adolescente , Taxa de Filtração Glomerular , Sistema Renina-Angiotensina/efeitos dos fármacosRESUMO
A new marker reflecting the pathophysiology of chronic kidney disease (CKD) has been desired for its therapy. In this study, we developed a virtual space where data in medical words and those of actual CKD patients were unified by natural language processing and category theory. A virtual space of medical words was constructed from the CKD-related literature (n = 165,271) using Word2Vec, in which 106,612 words composed a network. The network satisfied vector calculations, and retained the meanings of medical words. The data of CKD patients of a cohort study for 3 years (n = 26,433) were transformed into the network as medical-word vectors. We let the relationship between vectors of patient data and the outcome (dialysis or death) be a marker (inner product). Then, the inner product accurately predicted the outcomes: C-statistics of 0.911 (95% CI 0.897, 0.924). Cox proportional hazards models showed that the risk of the outcomes in the high-inner-product group was 21.92 (95% CI 14.77, 32.51) times higher than that in the low-inner-product group. This study showed that CKD patients can be treated as a network of medical words that reflect the pathophysiological condition of CKD and the risks of CKD progression and mortality.
Assuntos
Diálise Renal , Insuficiência Renal Crônica , Humanos , Estudos de Coortes , Progressão da Doença , Modelos de Riscos ProporcionaisRESUMO
BACKGROUND: Peritoneal dialysis (PD) is an essential lifesaving treatment for end-stage renal disease. However, PD therapy is limited by peritoneal inflammation, which leads to peritoneal membrane failure because of progressive peritoneal deterioration. Peritonitis is the most common complication in patients undergoing PD. Thus, elucidating the mechanism of chronic peritoneal inflammation after PD-associated peritonitis is an urgent issue for patients undergoing PD. This first case report suggests that an increased interleukin-1ß (IL-1ß) expression in the peritoneal dialysate after healing of peritonitis can contribute to peritoneal deterioration. CASE PRESENTATION: A 64-year-old woman was diagnosed with diabetes mellitus 10 years ago and had been started on PD for end-stage renal disease. One day, the patient developed PD-associated acute peritonitis and was admitted to our hospital for treatment. Thus, treatment with antimicrobial agents was initiated for PD-associated peritonitis. Dialysate turbidity gradually disappeared after treatment with antimicrobial agents, and the number of cells in the PD fluid decreased. After 2 weeks of antimicrobial therapy, peritonitis was clinically cured, and the patient was discharged. Thereafter, the patient did not develop peritonitis; however, residual renal function tended to decline, and peritoneal function also decreased in a relatively short period. We evaluated pro-inflammatory cytokine levels before and after PD-associated peritonitis; interestingly, the levels of IL-1ß remained high in the PD fluid, even after remission of bacterial peritonitis. In addition, it correlated with decreased peritoneal function. CONCLUSIONS: This case suggests that inflammasome-derived pro-inflammatory cytokines may contribute to chronic inflammation-induced peritoneal deterioration after PD-related peritonitis is cured.
Assuntos
Anti-Infecciosos , Falência Renal Crônica , Diálise Peritoneal , Peritonite , Feminino , Humanos , Pessoa de Meia-Idade , Interleucina-1beta , Diálise Peritoneal/efeitos adversos , Peritonite/tratamento farmacológico , Peritonite/etiologia , Peritonite/diagnóstico , Citocinas/metabolismo , Soluções para Diálise , Falência Renal Crônica/complicações , Inflamação/etiologiaRESUMO
During peritoneal dialysis (PD), the peritoneum is exposed to a bioincompatible dialysate, deteriorating the tissue and limiting the long-term effectiveness of PD. Peritoneal fibrosis is triggered by chronic inflammation induced by a variety of stimuli, including peritonitis. Exposure to PD fluid alters peritoneal macrophages phenotype. Inflammasome activation triggers chronic inflammation. First, it was determined whether inflammasome activation causes peritoneal deterioration. In the in vivo experiments, the increased expression of the inflammasome components, caspase-1 activity, and concomitant overproduction of IL-1ß and IL-18 were observed in a mouse model of peritoneal fibrosis. ASC-positive and F4/80-positive cells colocalized in the subperitoneal mesothelial cell layer. These macrophages expressed high CD44 levels indicating that the CD44-positive macrophages contribute to developing peritoneal deterioration. Furthermore, intravital imaging of the peritoneal microvasculature demonstrated that the circulating CD44-positive leukocytes may contribute to peritoneal fibrosis. Bone marrow transplantation in ASC-deficient mice suppressed inflammasome activation, thereby attenuating peritoneal fibrosis in a high glucose-based PD solution-injected mouse model. Our results suggest inflammasome activation in CD44-positive macrophages may be involved in developing peritoneal fibrosis. The inflammasome-derived pro-inflammatory cytokines might therefore serve as new biomarkers for developing encapsulating peritoneal sclerosis.
Assuntos
Fibrose Peritoneal , Peritonite , Animais , Camundongos , Peritônio , Inflamassomos , Modelos Animais de Doenças , InflamaçãoRESUMO
Chronic kidney disease is a common problem in the elderly and is associated with increased mortality. We have reported on the role of nitric oxide, which is generated from endothelial nitric oxide synthase (eNOS), in the progression of aged kidneys. To elucidate the role of endothelial dysfunction and the lack of an eNOS-NO pathway in ageing kidneys, we conducted experiments using eNOS and ASC-deficient mice. C57B/6 J mice (wild type (WT)), eNOS knockout (eNOS KO), and ASC knockout (ASC KO) mice were used in the present study. Then, eNOS/ASC double-knockout (eNOS/ASC DKO) mice were generated by crossing eNOS KO and ASC KO mice. These mice were sacrificed at 17-19 months old. The Masson positive area and the KIM-1 positive area tended to increase in eNOS KO mice, compared with WT mice, but not eNOS/ASC DKO mice. The COX-positive area was significantly reduced in eNOS KO mice, compared with WT and eNOS/ASC DKO mice. To determine whether inflammasomes were activated in infiltrating macrophages, the double staining of IL-18 and F4/80 was performed. IL-18 and F4/80 were found to be co-localised in the tubulointerstitial areas. Inflammasomes play a pivotal role in inflammaging in ageing kidneys. Furthermore, inflammasome activation may accelerate cellular senescence via mitochondrial dysfunction. The importance of endothelial function as a regulatory mechanism suggests that protection of endothelial function may be a potential therapeutic target.
Assuntos
Envelhecimento , Endotélio/fisiopatologia , Inflamassomos , Rim/fisiopatologia , Mitocôndrias/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Animais , Endotélio/enzimologia , Endotélio/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Mitocôndrias/fisiologia , Óxido Nítrico/metabolismo , Doenças Vasculares/fisiopatologiaRESUMO
Hypoxia-inducible factor prolyl-hydroxylase inhibitors belong to a new class of orally administered drugs for treating anemia in patients with chronic kidney disease (CKD). The prevalence of hypothyroidism is disproportionately high in patients with CKD on hemodialysis. We report a rapid suppression of thyroid-stimulating hormone (TSH) and decrease in free triiodothyronine (T3) and free tetraiodothyronine levels after switching from darbepoetin alfa to roxadustat in a hemodialysis patient with hypothyroidism on levothyroxine therapy. This was reversed after stopping roxadustat. Roxadustat has structural similarity with T3 and is a selective activating ligand for thyroid hormone receptor-ß possibly suppressing TSH release.
RESUMO
Serum zinc (Zn) levels tend to be low in chronic kidney disease (CKD) patients. This cohort study was conducted to investigate the relationship between zinc deficiency and CKD progression. Patients were classified into two groups based on Zn levels < 60 µg/dl (low-Zn group, n = 160) and ≥ 60 µg/dl (high-Zn group, n = 152). The primary outcome was defined as end-stage kidney disease (ESKD) or death and was examined over a 1-year observation period. Overall, the mean Zn level was 59.6 µg/dl and the median eGFR was 20.3 ml/min/1.73 m2. The incidence of the primary outcome was higher in the low-Zn group (p<0.001). Various Cox proportional hazards models adjusted for baseline characteristics showed higher risks of the primary outcome in the low-Zn group than in the high-Zn group. Competing risks analysis showed that low Zn levels were associated with ESKD but not with death. Moreover, in propensity score-matched analysis, the low-Zn group showed a higher risk of the primary outcome [adjusted hazard ratio 1.81 (95% confidence interval 1.02, 3.24)]. Furthermore, an interaction was observed between Zn and serum albumin levels (interaction p = 0.026). The results of this study indicate that zinc deficiency is a risk factor for CKD progression.
Assuntos
Hipoalbuminemia/sangue , Insuficiência Renal Crônica/sangue , Zinco/deficiência , Idoso , Idoso de 80 Anos ou mais , Progressão da Doença , Feminino , Taxa de Filtração Glomerular , Humanos , Hipoalbuminemia/etiologia , Japão/epidemiologia , Estimativa de Kaplan-Meier , Falência Renal Crônica/sangue , Falência Renal Crônica/etiologia , Falência Renal Crônica/mortalidade , Masculino , Pessoa de Meia-Idade , Pontuação de Propensão , Insuficiência Renal Crônica/complicações , Estudos Retrospectivos , Fatores de Risco , Zinco/fisiologiaRESUMO
It has been drawing much attention that type 2 diabetes mellitus is closely associated with increased incidence of numerous cancers and their poor prognosis. Consequently, malignancy has been recently recognized as one of diabetic complications in addition to various conventional complications. Furthermore, it is well known that the prevalence of renal cell carcinoma (RCC) is drastically increased in hemodialysis (HD) patients. Therefore, screening of RCCs in HD patients is a very important and urgent issue as there are no highly sensitive tumor markers for RCCs. Monochrome superb microvascular imaging (mSMI) is a relatively new Doppler ultrasound technique and is useful especially when evaluating very slow blood flow state, because this allows for imaging microvessels with low velocity in the absence of a contrast agent. Thus, mSMI might be also useful when contrast enhancement is not obvious on CT and/or contrast-enhanced ultrasonography using perflubutane or contrast agents are contraindicated. Moreover, it has been reported that mSMI could effectively detect vascularity of renal malignant tumor than benign renal mass in nondialysis patients. We propose that mSMI of ultrasonography could become one of the very useful methods for detecting RCCs at an early stage with high sensitivity in HD patients.
RESUMO
Peritoneal dialysis (PD) is valuable for patients starting on renal replacement therapy because it preserves residual renal function, maintains hemodynamic stability, and affords higher quality of life than hemodialysis. Amyloid-related kidney disease is a rare condition and a cause of end-stage renal disease, the incidence of which appears to be rising in recent years. Hemoperitoneum is a common complication of PD. In some cases, it requires urgent treatment and careful monitoring for deterioration and potential complications. Although the kidney is a retroperitoneal organ, renal hemorrhage can cause bloody peritoneal dialysate. We encountered a rare case of amyloid light-chain amyloidosis where bilateral perirenal hematoma occurred shortly after initiation of PD. Amyloid angiopathy with increased blood vessel fragility and impaired vasoconstriction may promote bleeding. Therefore, hemoperitoneum in a patient on PD with disease causing fragile blood vessels, such as amyloidosis, should alert the physician to the possibility of underlying angiopathy.
Assuntos
Amiloidose/diagnóstico , Hematoma/diagnóstico , Nefropatias/diagnóstico , Diálise Peritoneal/efeitos adversos , HumanosRESUMO
Endothelial dysfunction represents a predominant early feature of diabetes, rendering patients with diabetes prone to renal complications, e.g., proteinuria. Recent studies have indicated a possible role for xanthine oxidase (XO) in the pathogenesis of vascular dysfunctions associated with diabetes. In the present study, we investigated the contribution of XO activation on the progression of diabetic nephropathy in a mouse model using selective XO inhibitors. Male Ins2Akita heterozygous mice were used with wild-type mice as controls. Akita mice were treated with topiroxostat (Topi) or vehicle for 4 wk. Serum uric acid levels were significantly reduced in Akita + Topi mice compared with Akita + vehicle mice. The Akita + Topi group had a significant reduction in urinary albumin excretion compared with the Akita + vehicle group. Mesangial expansion, glomerular collagen type IV deposition, and glomerular endothelial injury (assessed by lectin staining and transmission electron microscopy) were considerably reduced in the Akita + topi group compared with the Akita + vehicle group. Furthermore, glomerular permeability was significantly higher in the Akita + vehicle group compared with the wild-type group. These changes were reduced with the administration of Topi. We conclude that XO inhibitors preserve glomerular endothelial functions and rescue compromised glomerular permeability, suggesting that XO activation plays a vital role in the pathogenesis of diabetic nephropathy.
Assuntos
Ameloblastos/metabolismo , Nefropatias Diabéticas/metabolismo , Glomérulos Renais/metabolismo , Xantina Oxidase/metabolismo , Albuminúria/metabolismo , Animais , Diabetes Mellitus Experimental/metabolismo , Modelos Animais de Doenças , Rim/metabolismo , Camundongos , NADPH Oxidases/metabolismo , Estresse Oxidativo/fisiologia , Ácido Úrico/metabolismoRESUMO
Southwestern Japan suffered its worst rains in 2018 causing floods and mudslides, claiming 225 lives and forcing millions for evacuations. Referred as "Heisei san-ju-nenshichi-gatsugou", the disaster was the result of incessant precipitation caused by the interaction of typhoon "Prapiroon" with the seasonal rain front "Baiu". The present epidemiological study aims to investigate disaster-induced health issues in 728 residents of Innoshima island in the Hiroshima Prefecture by comparing their clinical data in pre-disaster (2017) and disaster-hit (2018) years which was obtained from annual health screening. Comparison of data showed a significant increase in the urine protein concentration in victims following the disaster. Probing further into the household conditions, showed that a total of 59,844 households were affected with water outage during the heavy rains, which was accompanied by severe damage of sewerage pipelines with complete recovery process taking two weeks. This two weeks of the crisis forced victims to refrain from using restrooms which in turn led to infrequent urination, thereby explaining the increased urine protein concentration in victims following the disaster. The present study addresses the acute health implications caused by the water crisis and serves as a precautionary measure for disaster management council to provide enhanced aftercare services in victims in further events of natural disasters.
RESUMO
BACKGROUND: Long-term exposure to bioincompatible peritoneal dialysate causes the loss of mesothelial cells and accumulation of matrix proteins, leading to an increase in the thickness of the submesothelial layer, thereby limiting the long-term effectiveness of peritoneal dialysis (PD). However, the detailed molecular mechanisms underlying the process of peritoneal fibrosis have not been clearly elucidated. Wnt/ß-catenin signaling pathway activation has been suggested to play a pivotal role in the development of organ fibrosis. Moreover, Klotho protein can regulate Wnt/ß-catenin signaling. We examined the role of Klotho protein in reducing peritoneal fibrosis by inhibiting Wnt/ß-catenin signaling. METHODS: The ß-catenin-activated transgenic (BAT) driving expression of nuclear ß-galactosidase reporter transgenic (BAT-LacZ) mice, the alpha-Klotho gene under control of human elongation factor 1 alpha promoter [Klotho transgenic (KLTG) and C57BL/6 background] and C57BL/6 mice [wild-type (WT)] were used. The mice received daily intraperitoneal (i.p.) injections of 4.25% glucose with lactate (PD solution) or saline as a control for 4 weeks. Other mice received daily i.p. injections of the same volume of saline (normal control). RESULTS: After exposure to PD, Wnt signal activation was observed on the peritoneal mesothelial cells in WT-PD mice. The peritoneal fibrosis was also accelerated in WT-PD mice. The protein expression of ß-catenin and Wnt-inducible genes were also remarkably increased in WT-PD mice. On the other hand, KLTG-PD mice attenuated activation of Wnt/ß-catenin signaling after exposure to PD and ameliorated the progression of peritoneal fibrosis. CONCLUSIONS: Overexpression of Klotho protein protects the peritoneal membrane through attenuation of the Wnt/ß-catenin signaling pathway. The availability of recombinant Klotho protein would provide a novel potential therapeutic target in peritoneal fibrosis.
Assuntos
Glucuronidase/fisiologia , Fibrose Peritoneal/terapia , Proteínas Wnt/antagonistas & inibidores , beta Catenina/antagonistas & inibidores , Animais , Humanos , Proteínas Klotho , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Diálise Peritoneal/efeitos adversos , Fibrose Peritoneal/etiologia , Fibrose Peritoneal/patologia , Proteínas Wnt/metabolismo , beta Catenina/metabolismoRESUMO
Multiple clinical studies have shown that bardoxolone methyl, a potent activator of nuclear factor erythroid 2-related factor 2 (Nrf2), is effective in increasing glomerular filtration rate in patients with chronic kidney disease. However, whether an Nrf2 activator can protect tubules from proteinuria-induced tubular damage via anti-inflammatory and antioxidative stress mechanisms is unknown. Using an Institute of Cancer Research-derived glomerulonephritis (ICGN) mouse model of nephrosis, we examined the effects of dihydro-CDDO-trifluoroethyl amide (dh404), a rodent-tolerable bardoxolone methyl analog, in protecting the tubulointerstitium; dh404 markedly suppressed tubular epithelial cell damage in the renal interstitium of ICGN mice. The tubular epithelial cells of ICGN mice showed a decrease in the size and number of mitochondria, as well as the breakdown of the crista structure, whereas the number and ultrastructure of mitochondria were maintained by the dh404 treatment. To further determine the effect of dh404 on mitochondrial function, we used human proximal tubular cells in vitro. Stimulation with albumin and free fatty acid increased mitochondrial reactive oxygen species (ROS). However, dh404 administration diminished mitochondrial ROS. Our data show that dh404 significantly reduced proteinuria-induced tubular cell mitochondrial damage, suggesting that improved redox balance and mitochondrial function and suppression of inflammation underlie the cytoprotective mechanism of Nrf2 activators, including bardoxolone methyl, in diabetic kidney disease.-Nagasu, H., Sogawa, Y., Kidokoro, K., Itano, S., Yamamoto, T., Satoh, M., Sasaki, T., Suzuki, T., Yamamoto, M., Wigley, W. C., Proksch, J. W., Meyer, C. J., Kashihara, N. Bardoxolone methyl analog attenuates proteinuria-induced tubular damage by modulating mitochondrial function.
Assuntos
Túbulos Renais Proximais/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Ácido Oleanólico/análogos & derivados , Proteinúria/complicações , Animais , Células Cultivadas , Humanos , Túbulos Renais Proximais/patologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Mitocôndrias/fisiologia , Fator 2 Relacionado a NF-E2/fisiologia , Ácido Oleanólico/farmacologia , Espécies Reativas de Oxigênio/metabolismoRESUMO
BACKGROUND: Sodium glucose cotransporter 2 inhibitors may reduce kidney hyperfiltration, thereby preventing diabetic kidney disease progression, which may in turn reduce cardiovascular risk, including heart failure. However, the mechanisms that regulate renal function responses to sodium glucose cotransporter 2 inhibition are not yet fully understood. We explored the renal protective effects of sodium glucose cotransporter 2 inhibition with empagliflozin, with a focus on glomerular hemodynamic effects and tubuloglomerular feedback using in vivo multiphoton microscopy imaging techniques. METHODS: C57BL/6 mice and spontaneously diabetic Ins2+/Akita mice were studied. The mice were treated with empagliflozin (20 mg·kg-1·d-1) and insulin for 4 weeks, and the single-nephron glomerular filtration rate was measured using multiphoton microscope. A neuronal nitric oxide synthase inhibitor (7-nitroindazole, 20 mg·kg-1·d-1) or a cyclooxygenase-2 inhibitor (SC58236, 6 mg/L), or an A1 adenosine receptor antagonist (8-cyclopentyl-1,3-dipropylxanthine, 1 mg·kg-1·d-1) was administered to elucidate the mechanisms of tubuloglomerular feedback signaling and single-nephron glomerular filtration rate regulation. RESULTS: The urinary excretion of adenosine, nitric oxide metabolites, and the prostanoid prostaglandin E2 was also quantified. The single-nephron glomerular filtration rate in the Ins2+/Akita group was higher than in controls (C57BL/6; 4.9±1.3 nL/min versus Ins2+/Akita; 15.8±6.8 nL/min) and lower in Ins2+/Akita /empagliflozin to 8.0±3.3 nL/min (P<0.01). In vivo imaging also revealed concomitant afferent arteriolar dilation (P<0.01) and increased glomerular permeability of albumin in the Ins2+/Akita group. Empagliflozin ameliorated these changes (P<0.01). Urinary adenosine excretion in the Ins2+/Akita/empagliflozin group was higher than in Ins2+/Akita (Ins2+/Akita; 3.4±1.4 nmol/d, Ins2+/Akita/empagliflozin; 11.2±3.0 nmol/d, P<0.05), whereas nitric oxide metabolites and prostaglandin E2 did not differ. A1 adenosine receptor antagonism, but not neuronal nitric oxide synthase or cyclooxygenase-2 inhibition, blocked the effect of empagliflozin on renal function. Empagliflozin increased urinary adenosine excretion and reduced hyperfiltration via afferent arteriolar constriction, effects that were abolished by A1 adenosine receptor blockade. CONCLUSIONS: Adenosine/A1 adenosine receptor pathways play a pivotal role in the regulation of the single-nephron glomerular filtration rate via tubuloglomerular feedback mechanisms in response to sodium glucose cotransporter 2 inhibition, which may contribute to renal and cardiovascular protective effects reported in clinical trials.
Assuntos
Diabetes Mellitus Experimental/diagnóstico por imagem , Diabetes Mellitus Experimental/tratamento farmacológico , Técnicas In Vitro/métodos , Rim/fisiopatologia , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Animais , Compostos Benzidrílicos/farmacologia , Compostos Benzidrílicos/uso terapêutico , Glucosídeos/farmacologia , Glucosídeos/uso terapêutico , Humanos , Masculino , Camundongos , Inibidores do Transportador 2 de Sódio-Glicose/farmacologiaRESUMO
AIM: Acute kidney injury (AKI) is associated with chronic kidney disease, as well as high mortality, but effective treatments for AKI are still lacking. A recent study reported the prevention of renal injury, such as ischemia-reperfusion injury, by 5-aminolevulinic acid (ALA), which induces an antioxidant effect. The current study aimed to investigate the effect of ALA in a rhabdomyolysis-induced mouse model of AKI created by intramuscular injection of 50% glycerol. METHODS: Rhabdomyolysis-induced AKI was induced by an intramuscular injection of glycerol (5 mL/kg body weight) into mice. Administration of ALA (30 mg/kg, by gavage) was started from 48 h before or 24 h after glycerol injection. The mice were sacrificed at 72 h after glycerol injection. The roles of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1), which is one of the Nrf2-related antioxidants, were further investigated through in vivo and in vitro methods. RESULTS: 5-aminolevulinic acid markedly reduced renal dysfunction and tubular damage in mice with rhabdomyolysis-induced AKI. ALA administration decreased oxidative stress, macrophage infiltration, and inflammatory cytokines and apoptosis. The expression of Nrf2 was upregulated by ALA administration. However, administration of Zinc protoporphyrin-9 (ZnPPIX) to inhibit HO-1 activity did not abolish these improvements by ALA. The expression of Nrf2-associated antioxidant factors other than HO-1 was also increased. CONCLUSION: These findings indicate that ALA exerts its antioxidant activity via Nrf2-associated antioxidant factors to provide a renoprotective effect against rhabdomyolysis-induced AKI.
Assuntos
Injúria Renal Aguda/prevenção & controle , Ácido Aminolevulínico/farmacologia , Antioxidantes/farmacologia , Túbulos Renais/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/agonistas , Rabdomiólise/prevenção & controle , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/patologia , Animais , Apoptose/efeitos dos fármacos , Células Cultivadas , Citocinas/metabolismo , Citoproteção , Modelos Animais de Doenças , Glicerol , Heme Oxigenase-1/metabolismo , Humanos , Mediadores da Inflamação/metabolismo , Túbulos Renais/metabolismo , Túbulos Renais/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Camundongos Endogâmicos C57BL , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Rabdomiólise/induzido quimicamente , Rabdomiólise/metabolismo , Rabdomiólise/patologia , Transdução de Sinais/efeitos dos fármacosRESUMO
Hypertension causes vascular complications, such as stroke, cardiovascular disease, and chronic kidney disease (CKD). The relationship between endothelial dysfunction and progression of kidney disease is well known. However, the relationship between the eNOS-NO pathway and chronic inflammation, which is a common pathway for the progression of kidney disease, remains unexplored. We performed in vivo experiments to determine the role of the eNOS-NO pathway by using eNOS-deficient mice in a hypertensive kidney disease model. All mice were unilateral nephrectomized (Nx). One week after Nx, the mice were randomly divided into two groups: the aldosterone infusion groups and the vehicle groups. All mice also received a 1% NaCl solution instead of drinking water. The aldosterone infusion groups were treated with hydralazine to correct blood pressure differences. After four weeks of drug administration, all mice were euthanized, and blood and kidney tissue samples were collected. In the results, NLRP3 inflammasome activation was elevated in the kidneys of the eNOS-deficient mice, and tubulointerstitial fibrosis was accelerated. Suppression of inflammasome activation by knocking out ASC prevented tubulointerstitial injury in the eNOS knockout mice, indicating that the eNOS-NO pathway is involved in the development of kidney dysfunction through acceleration of NLRP3 inflammasome in macrophages. We revealed that endothelial function, particularly the eNOS-NO pathway, attenuates the progression of renal tubulointerstitial injury via suppression of inflammasome activation. Clinically, patients who develop vascular endothelial dysfunction have lifestyle diseases, such as hypertension or diabetes, and are known to be at risk for CKD. Our study suggests that the eNOS-NO pathway could be a therapeutic target for the treatment of chronic kidney disease associated with endothelial dysfunction.