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1.
Nephrol Dial Transplant ; 35(5): 773-781, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32221606

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.

2.
FASEB J ; 33(11): 12253-12263, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31431054

RESUMO

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.

3.
Circulation ; 140(4): 303-315, 2019 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-30773020

RESUMO

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.

4.
Nephrology (Carlton) ; 24(1): 28-38, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29068550

RESUMO

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
Lesão Renal Aguda/prevenção & controle , Ácido Aminolevulínico/farmacologia , Antioxidantes/farmacologia , Túbulos Renais/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/agonistas , Rabdomiólise/prevenção & controle , Lesão Renal Aguda/induzido quimicamente , Lesão Renal Aguda/metabolismo , Lesão 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 fármacos
5.
PLoS One ; 13(10): e0203823, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30281670

RESUMO

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.


Assuntos
Hipertensão Renal/metabolismo , Hipertensão/metabolismo , Inflamassomos/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Óxido Nítrico/metabolismo , Insuficiência Renal Crônica/metabolismo , Aldosterona/farmacologia , Animais , Anti-Hipertensivos/administração & dosagem , Modelos Animais de Doenças , Endotélio/patologia , Endotélio/fisiopatologia , Fibrose , Humanos , Hidralazina/administração & dosagem , Hipertensão/complicações , Hipertensão Renal/tratamento farmacológico , Hipertensão Renal/patologia , Inflamassomos/efeitos dos fármacos , Rim/patologia , Macrófagos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Terapia de Alvo Molecular , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Óxido Nítrico Sintase Tipo III/genética , Cultura Primária de Células , Insuficiência Renal Crônica/induzido quimicamente , Insuficiência Renal Crônica/etiologia , Insuficiência Renal Crônica/patologia , Vasodilatadores/administração & dosagem
6.
Sci Rep ; 7(1): 8801, 2017 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-28821730

RESUMO

Chronic inflammation can be a major driver of the failure of a variety of organs, including chronic kidney disease (CKD). The NLR family pyrin domain-containing 3 (NLRP3) inflammasome has been shown to play a pivotal role in inflammation in a mouse kidney disease model. Nuclear factor erythroid 2-related factor 2 (Nrf2), the master transcription factor for anti-oxidant responses, has also been implicated in inflammasome activation under physiological conditions. However, the mechanism underlying inflammasome activation in CKD remains elusive. Here, we show that the loss of Nrf2 suppresses fibrosis and inflammation in a unilateral ureter obstruction (UUO) model of CKD in mice. We consistently observed decreased expression of inflammation-related genes NLRP3 and IL-1ß in Nrf2-deficient kidneys after UUO. Increased infiltration of M1, but not M2, macrophages appears to mediate the suppression of UUO-induced CKD symptoms. Furthermore, we found that activation of the NLRP3 inflammasome is attenuated in Nrf2-deficient bone marrow-derived macrophages. These results demonstrate that Nrf2-related inflammasome activation can promote CKD symptoms via infiltration of M1 macrophages. Thus, we have identified the Nrf2 pathway as a promising therapeutic target for CKD.


Assuntos
Macrófagos/imunologia , Macrófagos/metabolismo , Fator 2 Relacionado a NF-E2/deficiência , Obstrução Ureteral/etiologia , Obstrução Ureteral/metabolismo , Animais , Modelos Animais de Doenças , Fibrose , Perfilação da Expressão Gênica , Inflamassomos/genética , Inflamassomos/metabolismo , Inflamação/etiologia , Inflamação/metabolismo , Inflamação/patologia , Rim/metabolismo , Rim/patologia , Ativação de Macrófagos/genética , Ativação de Macrófagos/imunologia , Camundongos , Camundongos Knockout , Obstrução Ureteral/patologia , Obstrução Ureteral/terapia
7.
Mol Med Rep ; 15(6): 4169-4175, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28487937

RESUMO

The present study aimed to assess the effects of colchicine, a known anti­inflammatory agent, on renal fibrosis using a murine model of unilateral ureteral obstruction (UUO). Male C57BL/6 mice were divided into two groups, vehicle­ and colchicine­treated. Colchicine (0.5 mg/kg/day) was administered by osmotic pump, and the UUO procedure was performed on the left kidney 7 days later. The mice were sacrificed at 14 days following UUO. Colchicine treatment suppressed interstitial fibrosis of the UUO kidneys. In addition, fibrogenic gene expression in the UUO kidneys was decreased by colchicine administration. NRK­49F normal rat kidney fibroblasts were cultured with or without colchicine under angiotensin II stimulation, following which a wound­healing assay and actin fiber staining were performed to evaluate the effects of colchicine in vitro. Colchicine was demonstrated to inhibit angiotensin II­induced fibroblast migration in vitro in a concentration­dependent manner. Colchicine treatment also suppressed the angiotensin II­induced activation of Ras homolog gene family member A in NRK­49F cells. In conclusion, colchicine treatment significantly inhibited fibroblast activity in vitro and attenuated renal fibrosis in vivo in UUO­operated mice. Therefore, the prevention of renal fibrosis following injury may represent a novel therapeutic application for colchicine.


Assuntos
Colchicina/farmacologia , Nefropatias/etiologia , Nefropatias/patologia , Obstrução Ureteral/complicações , Angiotensina II/metabolismo , Animais , Biomarcadores , Linhagem Celular , Movimento Celular , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibrose , Imuno-Histoquímica , Nefropatias/tratamento farmacológico , Masculino , Camundongos , Ratos , Proteína rhoA de Ligação ao GTP/metabolismo
8.
Contrib Nephrol ; 189: 246-251, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-27951575

RESUMO

BACKGROUNDS: Vascular access (VA) stenosis increases the risk of VA obstruction due to the gradual progress of intimal thickening. Therefore, we should try to detect VA stenosis early. However, we do not have a cutoff for when a difference between prescribed Kt/V and delivered Kt/V reflects a clinical issue. Thus, we have devised a new index, the 'clearance gap' (CL-Gap), which quantifies the difference between the effective clearance (eCL) of a hemodialysis (HD) patient and the theoretical clearance (tCL) of a dialyzer to detect a decrease in dialysis efficiency due to VA dysfunction. SUMMARY: We propose a qualitative technique of analyzing dialysis (the CL-Gap method) concerning Kt/V by estimating the eCL based on the delivered Kt/V and the difference with the tCL based on the dialyzer. When VA recirculation and blood removal failure occurs, the eCL decreases, and it is expected that the CL-Gap increases. On the contrary, if uniform internal removal occurs, the eCL rises when we overestimate the delivered Kt/V and the CL-Gap is expected to decrease. However, we cannot judge whether a high CL-Gap indicates VA dysfunction immediately because it is necessary to consider not only VA dysfunction, but also the effect of other factors on the CL-Gap. Key Messages: We believe that it is important to think about VA function in a qualitative manner when managing the dose using the CL-Gap to achieve better dialysis treatment.


Assuntos
Modelos Teóricos , Dispositivos de Acesso Vascular/normas , Velocidade do Fluxo Sanguíneo , Constrição Patológica/diagnóstico , Humanos , Diálise Renal/métodos
9.
J Renin Angiotensin Aldosterone Syst ; 17(2): 1470320315625704, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27216079

RESUMO

INTRODUCTION: We investigated the feasibility of using a fluorescence resonance energy transfer system to image enzymatic activity in order to evaluate the effects of aliskiren (a direct renin inhibitor) on diabetic nephropathy. MATERIALS AND METHODS: First, we induced diabetes in C57BL/6J mice using streptozotocin, then treated them with either aliskiren (25 mg/kg/day) or the angiotensin type 1 receptor blocker valsartan (15 mg/kg/day) for four weeks. Finally, we utilized renin fluorescence resonance energy transfer substrate to assess renin activity. RESULTS: Renin activity was much higher in the kidneys of diabetic mice compared to those of the non-diabetic control mice. While aliskiren inhibited this activity, valsartan did not. We noted that production of reactive oxygen species intensified and the bioavailability of nitric oxide diminished in the glomeruli of diabetic mice. Aliskiren and valsartan significantly ameliorated these effects. They suppressed glomerular production of reactive oxygen species and urinary albumin excretion. In fact, urinary albumin excretion in diabetic mice treated with aliskiren or valsartan was lower than that in untreated diabetic mice. Furthermore, aliskiren and valsartan significantly reduced glomerular permeability by maintaining the glomerular endothelial surface layer. CONCLUSION: Fluorescence resonance energy transfer could provide a new tool for evaluating tissue and plasma enzymatic activity.


Assuntos
Amidas/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Transferência Ressonante de Energia de Fluorescência , Fumaratos/farmacologia , Imageamento Tridimensional , Rim/efeitos dos fármacos , Albuminúria/sangue , Albuminúria/complicações , Albuminúria/tratamento farmacológico , Amidas/uso terapêutico , Animais , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/complicações , Estudos de Viabilidade , Fumaratos/uso terapêutico , Glomérulos Renais/efeitos dos fármacos , Substâncias Macromoleculares/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Óxido Nítrico/biossíntese , Permeabilidade/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Substâncias Protetoras/uso terapêutico , Renina/sangue , Superóxidos/metabolismo
10.
Clin Exp Nephrol ; 20(1): 134-42, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26026991

RESUMO

BACKGROUND: The prevalence of gastroesophageal reflux disease (GERD) symptoms has not been investigated in patients on maintenance hemodialysis in Japan, and few studies have reported the effect of proton pump inhibitors (PPIs) in hemodialysis patients with GERD symptoms. Here, we investigated the prevalence of GERD symptoms and the effects of the PPI esomeprazole on the quality of life related to reflux and dyspepsia in patients on maintenance hemodialysis. METHODS: This was a cross-sectional/cohort study of hemodialysis outpatients implemented in 10 Japanese medical facilities from October 2012 to March 2014. The trial was registered in the UMIN Clinical Trial Registry (UMIN000009124). RESULTS: Forty-one of 385 patients (11%) reported GERD symptoms on the Global Overall Symptom (GOS) questionnaire. Multivariate logistic regression analysis identified the independent prognostic factors for GERD symptoms as a history of gastric ulcer and use of sevelamer hydrochloride or calcium polystyrene sulfonate. Participants with GERD symptoms completed the Quality of Life in Reflux and Dyspepsia, Japanese version (QOLRAD-J) questionnaire and were assigned to receive 4-week esomeprazole treatment (20 mg/day). This PPI therapy significantly improved all QOLRAD-J domains in the full analysis set (n = 28) and improved the GERD symptoms listed in the GOS questionnaire. Significantly impaired disease-specific quality of life (QOL) in the QOLRAD-J domains was observed in 44.4-74.1% of patients who had symptoms before treatment. The mean GOS and QOLRAD-J scores correlated significantly. CONCLUSION: Therapy with 20 mg/day esomeprazole appears to be efficacious for improving disease-specific QOL and GERD symptoms in Japanese patients on maintenance hemodialysis.


Assuntos
Dispepsia/tratamento farmacológico , Esomeprazol/uso terapêutico , Refluxo Gastroesofágico/tratamento farmacológico , Nefropatias/terapia , Inibidores da Bomba de Prótons/uso terapêutico , Qualidade de Vida , Diálise Renal , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Dispepsia/diagnóstico , Dispepsia/epidemiologia , Dispepsia/psicologia , Esomeprazol/efeitos adversos , Feminino , Refluxo Gastroesofágico/diagnóstico , Refluxo Gastroesofágico/epidemiologia , Refluxo Gastroesofágico/psicologia , Humanos , Japão/epidemiologia , Nefropatias/diagnóstico , Nefropatias/epidemiologia , Nefropatias/psicologia , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Prevalência , Inibidores da Bomba de Prótons/efeitos adversos , Indução de Remissão , Inquéritos e Questionários , Fatores de Tempo , Resultado do Tratamento
11.
Clin Exp Nephrol ; 20(5): 671-678, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26586006

RESUMO

BACKGROUND: Expression of klotho, the renoprotective anti-aging gene, is decreased in diabetic model kidneys. We hypothesized that klotho protein attenuates renal hypertrophy and glomerular injury in a mouse model of diabetic nephropathy. METHODS: Klotho transgenic (KLTG) mice were crossed with spontaneously diabetic Ins2Akita (AKITA) mice. Glomerular morphology, macrophage infiltration, urinary albumin excretion and urinary 8-hydroxy-2-deoxy guanosine excretion were examined. In vitro, human glomerular endothelial cells were stimulated with high glucose with or without recombinant klotho, and calpain activity and proinflammatory cytokine expressions were measured. RESULTS: We found that klotho protein overexpression attenuates renal hypertrophy and glomerular injury in this mouse model of diabetic nephropathy. Klotho overexpression attenuated renal hypertrophy, albuminuria, glomerular mesangial expansion, and endothelial glycocalyx loss in the AKITA mice. AKITA mice exhibit high levels of urinary 8-hydroxy-2-deoxy guanosine excretion. In the presence of klotho overexpression, this effect was reversed. In addition, the glomerular macrophage infiltration characteristic of AKITA mice was attenuated in KLTG-AKITA mice. In human glomerular endothelial cells, high glucose induced calpain activity. This effect was suppressed by expression of recombinant klotho, which also suppressed the induction of proinflammatory cytokines. CONCLUSION: Our data suggest klotho protein protects against diabetic nephropathy through multiple pathways.


Assuntos
Diabetes Mellitus/metabolismo , Nefropatias Diabéticas/prevenção & controle , Glucuronidase/metabolismo , Glomérulos Renais/metabolismo , Albuminúria/genética , Albuminúria/metabolismo , Albuminúria/prevenção & controle , Animais , Biomarcadores/urina , Calpaína/genética , Calpaína/metabolismo , Células Cultivadas , Desoxiguanosina/análogos & derivados , Desoxiguanosina/urina , Diabetes Mellitus/genética , Nefropatias Diabéticas/genética , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Modelos Animais de Doenças , Genótipo , Glucose/metabolismo , Glucuronidase/genética , Humanos , Hipertrofia , Mediadores da Inflamação/metabolismo , Glomérulos Renais/patologia , Macrófagos/metabolismo , Macrófagos/patologia , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fenótipo , Transfecção
12.
Lab Invest ; 96(1): 25-36, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26552047

RESUMO

Increased generation of reactive oxygen species (ROS) is a common denominative pathogenic mechanism underlying vascular and renal complications in diabetes mellitus. Endothelial NAD(P)H oxidase is a major source of vascular ROS, and it has an important role in endothelial dysfunction. We hypothesized that activation of endothelial NAD(P)H oxidase initiates and worsens the progression of diabetic nephropathy, particularly in the development of albuminuria. We used transgenic mice with endothelial-targeted overexpression of the catalytic subunit of NAD(P)H oxidase, Nox2 (NOX2TG). NOX2TG mice were crossed with Akita insulin-dependent diabetic (Akita) mice that develop progressive hyperglycemia. We compared the progression of diabetic nephropathy in Akita versus NOX2TG-Akita mice. NOX2TG-Akita mice and Akita mice developed significant albuminuria above the baseline at 6 and 10 weeks of age, respectively. Compared with Akita mice, NOX2TG-Akita mice exhibited higher levels of NAD(P)H oxidase activity in glomeruli, developed glomerular endothelial perturbations, and attenuated expression of glomerular glycocalyx. Moreover, in contrast to Akita mice, the NOX2TG-Akita mice had numerous endothelial microparticles (blebs), as detected by scanning electron microscopy, and increased glomerular permeability. Furthermore, NOX2TG-Akita mice exhibited distinct phenotypic changes in glomerular mesangial cells expressing α-smooth muscle actin, and in podocytes expressing increased levels of desmin, whereas the glomeruli generated increased levels of ROS. In conclusion, activation of endothelial NAD(P)H oxidase in the presence of hyperglycemia initiated and exacerbated diabetic nephropathy characterized by the development of albuminuria. Moreover, ROS generated in the endothelium compounded glomerular dysfunctions by altering the phenotypes of mesangial cells and compromising the integrity of the podocytes.


Assuntos
Diabetes Mellitus Experimental/metabolismo , Nefropatias Diabéticas/metabolismo , NADPH Oxidases/metabolismo , Animais , Glicemia/análise , Diabetes Mellitus Experimental/enzimologia , Nefropatias Diabéticas/enzimologia , Feminino , Taxa de Filtração Glomerular/fisiologia , Glomérulos Renais/química , Glomérulos Renais/metabolismo , Glomérulos Renais/patologia , Masculino , Camundongos , Podócitos/química , Espécies Reativas de Oxigênio/metabolismo
13.
FASEB J ; 29(9): 3899-910, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26054366

RESUMO

High levels of aldosterone impair renal function by activating proinflammatory and profibrotic pathways. However, the molecular mechanism underlying aldosterone-induced inflammation and fibrosis is unknown. Inflammasome activation contributes to chronic kidney disease. We hypothesized that aldosterone induces renal tubulointerstitial inflammation and fibrosis by activating the inflammasome. Infusing wild-type mice with aldosterone (0.25 mg/kg/d) caused tubulointerstitial damage, increased expression of inflammasome components, caspase 1 activation, and overproduction of IL-1ß and IL-18. These changes were suppressed by eplerenone treatment (100 mg/kg/d) in wild-type mice or in mice deficient in apoptosis-associated speck-like protein with a caspase-recruitment domain (ASC). Caspase 1-positive and F4/80-positive cells colocalized in the interstitium. Bone marrow transplantation using ASC-deficient mice indicated that inflammasome activation in macrophages mediated aldosterone-induced renal fibrosis. IL-18 was detected in culture supernatants of macrophages treated with aldosterone, and mitochondria-derived reactive oxygen species activated the inflammasome in these macrophages. Our results indicate that exposure of macrophages to high levels of aldosterone resulted in the activation of inflammasomes via the mitochondria-derived reactive oxygen species. Thus, inflammasome activation in macrophages may serve as a new therapeutic target for chronic kidney disease.


Assuntos
Aldosterona/efeitos adversos , Inflamassomos/metabolismo , Nefropatias/metabolismo , Transdução de Sinais/efeitos dos fármacos , Aldosterona/farmacologia , Animais , Proteínas Reguladoras de Apoptose/biossíntese , Proteínas Reguladoras de Apoptose/genética , Proteínas Adaptadoras de Sinalização CARD , Caspase 1/biossíntese , Caspase 1/genética , Ativação Enzimática/efeitos dos fármacos , Ativação Enzimática/genética , Fibrose , Regulação da Expressão Gênica/efeitos dos fármacos , Inflamassomos/genética , Interleucina-18/biossíntese , Interleucina-18/genética , Interleucina-1beta/biossíntese , Interleucina-1beta/genética , Nefropatias/induzido quimicamente , Nefropatias/genética , Nefropatias/patologia , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Camundongos , Camundongos Knockout , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/genética
14.
Nephrology (Carlton) ; 20(9): 585-90, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25854541

RESUMO

AIM: Hypertension contributes critically to the development of renal arteriolosclerosis in chronic kidney disease (CKD), but the impact of vascular function indexes including central blood pressure on renal arteriolosclerosis has not been investigated. We determined whether vascular function indexes were related to renal arteriolosclerosis and renal clinical outcomes in CKD. METHODS: This cross-sectional study was implemented in our hospital. Subjects were in-patients with CKD aged ≥20 years who underwent a renal biopsy. Vascular function indexes included central systolic blood pressure (SBP), cardio-ankle vascular index (CAVI), and renal resistive index. Central SBP was measured non-invasively using an automated device. Arteriolosclerosis was assessed histologically. Renal clinical outcomes included estimated glomerular filtration rate using serum creatinine (eGFRcreat) or cystatin C (eGFRcys), and the urinary albumin-creatinine ratio. RESULTS: Among vascular function indexes, central SBP was weakly correlated with renal arteriolosclerosis (n = 55). Renal arteriolosclerosis was increased in hypertensive or hyperuricaemic patients, and negatively correlated with serum high-density lipoprotein (HDL) cholesterol and eGFRcys, which were independent risk factors for renal arteriolosclerosis in a stepwise multivariate regression analysis. Of the vascular function indexes, CAVI showed the strongest correlation with all renal clinical outcomes. Central SBP was correlated with only urinary albumin-creatinine ratio, while renal resistive index was correlated with eGFRcreat and urinary albumin-creatinine ratio. CONCLUSION: Decreased serum HDL cholesterol was independently and most closely associated with renal arteriolosclerosis. Of the vascular function indexes, CAVI had the greatest impact on renal clinical outcomes, although it was not associated with renal arteriolosclerosis.


Assuntos
Arteriolosclerose/fisiopatologia , Hemodinâmica , Rim/fisiopatologia , Obstrução da Artéria Renal/fisiopatologia , Insuficiência Renal Crônica/fisiopatologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Índice Tornozelo-Braço , Arteriolosclerose/diagnóstico , Biomarcadores/sangue , Biópsia , Pressão Sanguínea , Creatinina/sangue , Estudos Transversais , Cistatina C/sangue , Feminino , Taxa de Filtração Glomerular , Humanos , Hiperlipidemias/fisiopatologia , Hipertensão/fisiopatologia , Hiperuricemia/fisiopatologia , Rim/patologia , Masculino , Pessoa de Meia-Idade , Obstrução da Artéria Renal/diagnóstico , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/diagnóstico , Resistência Vascular , Adulto Jovem
15.
Clin Exp Nephrol ; 19(4): 567-75, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25216785

RESUMO

BACKGROUND: Long-term peritoneal dialysis (PD) causes peritoneal dysfunction and structural alterations, eventually leading to peritoneal fibrosis. The endothelial nitric oxide synthase (eNOS)-NO signaling pathway contributes to the progression of organ fibrosis. However, it remains unknown whether NO signaling is involved in the process of peritoneal fibrosis. We evaluated the role of the eNOS-NO signaling pathway in the development of peritoneal fibrosis and whether stimulation of soluble guanylate cyclase (sGC), a downstream effector of NO, could attenuate peritoneal fibrosis. METHODS: We used wild-type (WT) and eNOS-deficient mice (eNOSKO). The mice underwent mechanical peritoneal stripping-induced peritoneal fibrosis at day 0. At 3, 7, 14, and 28 days after peritoneal stripping, the mice were killed. In some eNOSKO mice, the sGC stimulator Bay 41-2272 was administered by intraperitoneal injection. RESULTS: In WT mice, granulomatous tissue formation was observed in the submesothelial area at days 3 and 7. After day 7, the peritoneal membrane thickness gradually decreased and peritoneal tissue was repaired with leaving only slight fibrosis at day 28. However, eNOSKO mice demonstrated more progression of peritoneal fibrosis than WT mice at 28 days after peritoneal stripping. Expression of vimentin in the thickened peritoneum was prolonged after day 7 in eNOSKO mice. Treatment with Bay 41-2272 significantly attenuated peritoneal vimentin expression and fibrosis in the eNOSKO mice. CONCLUSIONS: Disruption of the eNOS-NO signaling pathway exacerbates peritoneal fibrosis by delaying wound healing. sGC stimulation may be a useful therapy for prevention of peritoneal fibrosis.


Assuntos
Guanilato Ciclase/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Óxido Nítrico/metabolismo , Fibrose Peritoneal/enzimologia , Receptores Citoplasmáticos e Nucleares/metabolismo , Animais , Fibrose , Isoenzimas/metabolismo , Queratinas/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Diálise Peritoneal/efeitos adversos , Fibrose Peritoneal/etiologia , Fibrose Peritoneal/prevenção & controle , Peritônio/enzimologia , Peritônio/patologia , Transdução de Sinais , Guanilil Ciclase Solúvel , Vimentina/metabolismo
16.
Clin Exp Hypertens ; 36(3): 159-64, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-23786428

RESUMO

Abstract Hypertensive patients have a higher incidence of new-onset diabetic mellitus than normotensive subjects, and we hypothesized that hypertension induces morphological changes in islets via vascular injury. To test our hypothesis, we administrated hydralazine or irbesartan to spontaneously hypertensive stroke-prone (SHRsp) rats. A greater islet fibrosis was observed in SHRsp rats compared with controls, and irbesartan significantly ameliorated the fibrosis. High fat diet induced glucose intorelance in SHRsp rats and irbesartan but not hydralazine improved glucose torelance. We demonstrate islet morphological changes in hypertensive rats, and our data suggest that angiotensin receptor blockers have the potential to prevent islet injury.


Assuntos
Anti-Hipertensivos/farmacologia , Hipertensão/complicações , Ilhotas Pancreáticas/patologia , Estado Pré-Diabético/complicações , Lesões do Sistema Vascular , Animais , Compostos de Bifenilo/farmacologia , Pressão Sanguínea/fisiologia , Modelos Animais de Doenças , Hidralazina/farmacologia , Hipertensão/fisiopatologia , Irbesartana , Ilhotas Pancreáticas/efeitos dos fármacos , Masculino , Ratos Endogâmicos SHR , Tetrazóis/farmacologia , Lesões do Sistema Vascular/induzido quimicamente
17.
Microcirculation ; 21(2): 112-23, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24102788

RESUMO

OBJECTIVE: Angiotensin II causes potent increases in systemic and local pressure through its vasoconstrictive effect. Despite the importance of angiotensin II for local blood flow regulation, whether angiotensin II regulates the pancreatic islet microcirculation remains incompletely understood. We hypothesized that angiotensin II directly regulates the pancreatic islet microcirculation and thereby regulates insulin secretion. The aims of this study were to develop a new technique to visualize pancreatic islet hemodynamic changes in vivo and to analyze changes in islet circulation induced by angiotensin II or an angiotensin type 1 receptor blocker. METHODS: Using an in vivo imaging method, we observed the pancreatic islet microcirculation. Various doses of angiotensin II or an angiotensin type 1 receptor blocker were injected intravenously, and changes in islet microcirculation were observed. Glucose-stimulated insulin secretion from the pancreas was measured from the hepatic portal vein. RESULTS: We identified islet microcirculation using a fluorescent dye. Angiotensin II significantly induced blood vessel contraction in the islets in a dose-dependent manner. In contrast, the angiotensin type 1 receptor blocker induced vasodilation. Glucose-stimulated insulin secretion was decreased by angiotensin II infusion. CONCLUSIONS: These results show that angiotensin II is involved in the regulation of pancreatic islet microcirculation and insulin secretion.


Assuntos
Angiotensina II/farmacologia , Insulina/metabolismo , Ilhotas Pancreáticas , Vasoconstritores/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Secreção de Insulina , Ilhotas Pancreáticas/irrigação sanguínea , Ilhotas Pancreáticas/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Vasoconstrição/efeitos dos fármacos
18.
BMC Nephrol ; 14: 91, 2013 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-23601138

RESUMO

BACKGROUND: We describe a case of a fever of unknown etiology that was caused by a caseating tubercle granuloma which produced erythropoietin. To our knowledge, this is the first report of an erythropoietin- producing granuloma. CASE PRESENTATION: A 48-year-old Japanese man with a 5-year history of maintenance hemodialysis for diabetic nephropathy presented with an intermittent fever over a few months. During febrile periods he developed erythema nodosum on his legs. Computed tomography showed axillary lymph node enlargement and this was further corroborated by a gallium scan that revealed high gallium uptake in these nodes. A Mantoux test was positive and an interferongamma release assay for tuberculosis diagnosis was also positive. Lymph node tuberculosis was suspected and the patient underwent lymphadenectomy. Histological analysis of the lymph nodes revealed a caseating granuloma that showed positive results on an acid-fast bacteria stain and a Mycobacterium tuberculosis polymerase chain reaction test. After lymphadenectomy, however, the patient's hemoglobin levels rapidly decreased from 144 to 105 g/L, and this was further compounded by a decrease in serum erythropoietin from 223 mIU/mL to 10.7 mIU/mL by postoperative day 21. We suspected the tubercle to be a source of the erythropoietin and this was further confirmed by in situ hybridization. CONCLUSIONS: We report for the first time ectopic erythropoietin production by a tuberculous lymph node. Our observations are substantiated by a postoperative decline in his erythropoietin level and a clinical requirement for erythropoietin treatment.


Assuntos
Eritropoetina/metabolismo , Granuloma/diagnóstico , Granuloma/metabolismo , Diálise Renal , Tuberculose dos Linfonodos/diagnóstico , Tuberculose dos Linfonodos/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Diálise Renal/tendências
19.
J Am Soc Nephrol ; 24(7): 1139-50, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23620395

RESUMO

In diabetes, endothelial nitric oxide synthase (eNOS) produces superoxide anion rather than nitric oxide, referred to as "eNOS uncoupling," which may contribute to endothelial dysfunction, albuminuria, and diabetic nephropathy. Reduced levels of endothelium-derived tetrahydrobiopterin (BH4), an essential cofactor for eNOS, promote eNOS uncoupling. Accelerated degradation of guanosine triphosphate cyclohydrolase I (GTPCH I), the rate-limiting enzyme in BH4 biosynthesis, also occurs in diabetes, suggesting that GTPCH I may have a role in diabetic microvascular disease. Here, we crossed endothelium-dominant GTPCH I transgenic mice with Ins2(+/Akita) diabetic mice and found that endothelial overexpression of GTPCH I led to higher levels of intrarenal BH4 and lower levels of urinary albumin and reactive oxygen species compared with diabetic control mice. Furthermore, GTPCH I overexpression attenuated the hyperpermeability of macromolecules observed in diabetic control mice. In addition, we treated Ins2(+/Akita) mice with metformin, which activates AMP-activated protein kinase (AMPK) and thereby slows the degradation of GTPCH I; despite blood glucose levels that were similar to untreated mice, those treated with metformin had significantly less albuminuria. Similarly, in vitro, treating human glomerular endothelial cells with AMPK activators attenuated glucose-induced reductions in phospho-AMPK, GTPCH I, and coupled eNOS. Taken together, these data suggest that maintenance of endothelial GTPCH I expression and the resulting improvement in BH4 biosynthesis ameliorate diabetic nephropathy.


Assuntos
Biopterina/análogos & derivados , Diabetes Mellitus Experimental/metabolismo , Nefropatias Diabéticas/metabolismo , GTP Cicloidrolase/metabolismo , Albuminúria/metabolismo , Animais , Biopterina/metabolismo , Linhagem Celular , Endotélio Vascular/metabolismo , Humanos , Metformina/farmacologia , Camundongos , Óxido Nítrico Sintase Tipo III/metabolismo , Espécies Reativas de Oxigênio/metabolismo
20.
Clin Exp Nephrol ; 17(2): 155-73, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23385776

RESUMO

The Japan Renal Biopsy Registry (J-RBR) was started in 2007 and the Japan Kidney Disease Registry (J-KDR) was then started in 2009 by the Committee for Standardization of Renal Pathological Diagnosis and the Committee for the Kidney Disease Registry of the Japanese Society of Nephrology. The purpose of this report is to describe and summarize the registered data from 2009 and 2010. For the J-KDR, data were collected from 4,016 cases, including 3,336 (83.1 %) by the J-RBR and 680 (16.9 %) other cases from 59 centers in 2009, and from 4,681 cases including 4,106 J-RBR cases (87.7 %) and 575 other cases (12.3 %) from 94 centers in 2010, including the affiliate hospitals. In the J-RBR, 3,165 native kidneys (94.9 %) and 171 renal grafts (5.1 %) and 3,869 native kidneys (94.2 %) and 237 renal grafts (5.8 %) were registered in 2009 and 2010, respectively. Patients younger than 20 years of age comprised 12.1 % of the registered cases, and those 65 years and over comprised 24.5 % of the cases with native kidneys in 2009 and 2010. The most common clinical diagnosis was chronic nephritic syndrome (55.4 % and 50.0 % in 2009 and 2010, respectively), followed by nephrotic syndrome (22.4 % and 27.0 %); the most frequent pathological diagnosis as classified by the pathogenesis was IgA nephropathy (31.6 % and 30.4 %), followed by primary glomerular diseases (except IgA nephropathy) (27.2 % and 28.1 %). Among the primary glomerular diseases (except IgA nephropathy) in the patients with nephrotic syndrome, membranous nephropathy was the most common histopathology in 2009 (40.3 %) and minor glomerular abnormalities (50.0 %) were the most common in 2010 in native kidneys in the J-RBR. Five new secondary and longitudinal research studies by the J-KDR were started in 2009 and one was started in 2010.


Assuntos
Biópsia , Nefropatias/patologia , Rim/patologia , Sistema de Registros/normas , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Biópsia/normas , Feminino , Glomerulonefrite por IGA/patologia , Humanos , Japão/epidemiologia , Nefropatias/diagnóstico , Nefropatias/epidemiologia , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Pacientes , Padrões de Referência , Fatores Sexuais , Adulto Jovem
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