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BACKGROUND: Diabetic kidney disease (DKD) is associated with a higher risk of cardiovascular disease (CVD). Pentoxifylline (PTF), a nonselective phosphodiesterase inhibitor with anti-inflammatory, antiproliferative, and antifibrotic actions, has demonstrated renal benefits in both clinical trials and meta-analyses. The present work aimed to study the effects of PTF on the progression of subclinical atherosclerosis (SA) in a population of patients with diabetes and moderate to severe chronic kidney disease (CKD). METHODS: In this open-label, randomized controlled, prospective single-center pilot study the evolution of carotid intima-media thickness (CIMT) and ankle-brachial index (ABI) were determined in 102 patients with type 2 diabetes mellitus and CKD assigned to PTF, aspirin or control groups during 18 months. We also determined the variations in the levels of inflammatory markers and Klotho (KL), a protein involved in maintaining cardiovascular health, and their relationship with the progression of SA. RESULTS: Patients treated with PTF presented a better evolution of CIMT, increased KL mRNA levels in peripheral blood cells (PBCs) and reduced the inflammatory state. The progression of CIMT values was inversely related to variations in KL both in serum and mRNA expression levels in PBCs. Multiple regression analysis demonstrated that PTF treatment and variations in mRNA KL expression in PBCs, together with changes in HDL, were significant determinants for the progression of CIMT (adjusted R2 = 0.24, P < 0.001) independently of traditional risk factors. Moreover, both variables constituted protective factors against a worst progression of CIMT [OR: 0.103 (P = 0.001) and 0.001 (P = 0.005), respectively]. CONCLUSIONS: PTF reduced SA progression assessed by CIMT variation, a beneficial effect related to KL gene expression in PBCs. TRIAL REGISTRATION: The study protocol code is PTF-AA-TR-2009 and the trial was registered on the European Union Drug Regulating Authorities Clinical Trials (EudraCT #2009-016595-77). The validation date was 2010-03-09.
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Espessura Intima-Media Carotídea , Diabetes Mellitus Tipo 2 , Progressão da Doença , Pentoxifilina , Insuficiência Renal Crônica , Humanos , Projetos Piloto , Masculino , Pessoa de Meia-Idade , Pentoxifilina/uso terapêutico , Feminino , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/complicações , Estudos Prospectivos , Idoso , Resultado do Tratamento , Fatores de Tempo , Nefropatias Diabéticas/diagnóstico , Nefropatias Diabéticas/tratamento farmacológico , Glucuronidase/sangue , Glucuronidase/genética , Biomarcadores/sangue , Doenças das Artérias Carótidas/diagnóstico por imagem , Doenças das Artérias Carótidas/tratamento farmacológico , Doenças Assintomáticas , Mediadores da Inflamação/sangue , Inibidores de Fosfodiesterase/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Aterosclerose/tratamento farmacológico , Aterosclerose/diagnóstico , OsteocalcinaRESUMO
Introduction: Klotho protein is predominantly expressed in the kidneys and has also been detected in vascular tissue and peripheral blood circulating cells to a lesser extent. Carotid artery intima-media thickness (CIMT) burden, a marker of subclinical atherosclerosis, has been associated with reductions in circulating Klotho levels in chronic kidney disease patients, who show reduced levels of this protein at all stages of the disease. However, the contribution of serum Klotho and its expression levels in peripheral blood circulating cells and in the carotid artery wall on the CIMT in the absence of kidney impairment has not yet been evaluated. Methods: We conducted a single-center study in 35 atherosclerotic patients with preserved kidney function (eGFR≥60 mL/min/1.73m2) subjected to elective carotid surgery. Serum levels of Klotho and cytokines TNFa, IL6 and IL10 were determined by ELISA and transcripts encoding for Klotho (KL), TNF, IL6 and IL10 from vascular segments were measured by qRT-PCR. Klotho protein expression in the intima-media and adventitia areas was analyzed using immunohistochemistry. Results: APatients with higher values of CIMT showed reduced Klotho levels in serum (430.8 [357.7-592.9] vs. 667.8 [632.5-712.9] pg/mL; p<0.001), mRNA expression in blood circulating cells and carotid artery wall (2.92 [2.06-4.8] vs. 3.69 [2.42-7.13] log.a.u., p=0.015; 0.41 [0.16-0.59] vs. 0.79 [0.37-1.4] log.a.u., p=0.013, respectively) and immunoreactivity in the intimal-medial area of the carotids (4.23 [4.15-4.27] vs. 4.49 [4.28-4.63] log µm2 p=0.008). CIMT was inversely related with Klotho levels in serum (r= -0.717, p<0.001), blood mRNA expression (r=-0.426, p=0.011), and with carotid artery mRNA and immunoreactivity levels (r= -0.45, p=0.07; r= -0.455, p= 0.006, respectively). Multivariate analysis showed that serum Klotho, together with the gene expression levels of tumor necrosis factor TNFa in blood circulating cells, were independent determinants of CIMT values (adjusted R2 = 0.593, p<0.001). Discussion: The results of this study in subjects with eGFR≥60mL/min/1.73m2 show that patients with carotid artery atherosclerosis and higher values of CIMT present reduced soluble Klotho levels, as well as decreased KL mRNA expression in peripheral blood circulating cells and Klotho protein levels in the intima-media of the carotid artery wall.
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Aterosclerose , Doenças das Artérias Carótidas , Humanos , Espessura Intima-Media Carotídea , Interleucina-10 , Interleucina-6 , Rim/fisiologiaRESUMO
Diabetic kidney disease is one of the most frequent complications in patients with diabetes and constitutes a major cause of end-stage kidney disease. The prevalence of diabetic kidney disease continues to increase as a result of the growing epidemic of diabetes and obesity. Therefore, there is mounting urgency to design and optimize novel strategies and drugs that delay the progression of this pathology and contain this trend. The new approaches should go beyond the current therapy focussed on the control of traditional risk factors such as hyperglycaemia and hypertension. In this scenario, drug repurposing constitutes an economic and feasible approach based on the discovery of useful activities for old drugs. Pentoxifylline is a nonselective phosphodiesterase inhibitor currently indicated for peripheral artery disease. Clinical trials and meta-analyses have shown renoprotection secondary to anti-inflammatory and antifibrotic effects in diabetic patients treated with this old known drug, which makes pentoxifylline a candidate for repurposing in diabetic kidney disease.
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Cardiovascular disease is the leading cause of death worldwide. New therapeutic strategies are aimed to modulate the athero-inflammatory process that partially orchestrates underlying vascular damage. Peripheral blood circulating cells include different immune cells with a central role in the development of the atherogenic inflammatory response. The anti-aging protein α-Klotho has been related to protective effects against CVD. KL is expressed in monocytes, macrophages, and lymphocytes where it exerts anti-inflammatory effects. In this work, we analyse the relationships of the levels of inflammatory markers with the expression of the KL gene in PBCCs and with the serum levels of soluble KL in atherosclerotic vascular disease. For this, we conducted a cross-sectional single-center case-control study including a study group of 76 CVD patients and a control group of 16 cadaveric organ donors without medical antecedent or study indicating CVD. Vascular artery fragments and whole blood and serum samples were obtained during elective or organ retrieval surgery. Serum levels of sKL, TNFα and IL10, and gene expression levels of KL, TNF, IL10, NFKB1, DNMT1, and DNMT3A in PBCCs were measured. In these cells, we also determined KL promoter methylation percentage. Histological and immunohistochemical analyses were employed to visualize atherosclerotic lesions and to measure IL10 and TNFα levels in vascular fragments. Patients with CVD presented higher values of proinflammatory markers both at systemic and in the vasculature and in the PBCCs, compared to the control group. In PBCCs, CVD patients also presented lower gene expression levels of KL gene (56.4% difference, P < 0.001), higher gene expression levels of DNMT1 and DNMT3A (P < 0.0001, for both) and a higher methylation status of in the promoter region of KL (34.1 ± 4.1% vs. 14.6 ± 3.4%, P < 0.01). In PBCCs and vasculature, KL gene expression correlated inversely with pro-inflammatory markers and directly with anti-inflammatory markers. sKL serum levels presented similar associations with the expression levels of pro- and anti-inflammatory markers in PBCCs. The differences in KL expression levels in PBCCs and in serum sKL levels with respect to control group was even greater in those CVD patients with macroscopically observable atheromatous plaques. We conclude that promoter methylation-mediated downregulation of KL gene expression in PBCCs is associated with the pro-inflammatory status in atherosclerotic vascular disease.
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Aterosclerose , Doenças Cardiovasculares , Aterosclerose/genética , Biomarcadores , Estudos de Casos e Controles , Estudos Transversais , Glucuronidase/metabolismo , Humanos , Inflamação/genética , Inflamação/metabolismo , Interleucina-10 , Proteínas Klotho , Fator de Necrose Tumoral alfa/genéticaRESUMO
Chronic kidney disease (CKD) has been associated with a higher risk of cardiovascular disease (CVD). CKD patients present a decrease in the levels of the protein Klotho that accompanies the decrease in kidney function. This protein has been related to protective effects against CVD. However, it is unclear whether circulating Klotho, and its expression in peripheral blood cells (PBCs) are also associated with subclinical atherosclerosis in CKD. The present study aimed to study the relationship between Klotho and subclinical atherosclerosis in a population of patients with moderate to severe CKD. We determined the serum levels and gene expression in PBCs levels of Klotho and three inflammatory cytokines in 103 patients with CKD and investigated their relationship with two surrogate markers of subclinical atherosclerotis: ankle-brachial index (ABI) and carotid intima-media thickness (CIMT). Patients with subclinical atherosclerosis presented lower serum and PBCs expression levels of Klotho. Both variables were associated with the presence of subclinical atherosclerosis, being directly related with ABI and inversely with CIMT (P < 0.0001 for both). Multiple regression analysis demonstrated that both variables were significant determinants for ABI (adjusted R2 = 0.511, P < 0.0001) and CIMT (adjusted R2 = 0.445, P < 0.0001), independently of traditional and emergent cardiovascular risk factors. Moreover, both constituted protective factors against subclinical atherosclerosis [OR: 0.993 (P = 0.002) and 0.231 (P = 0.025), respectively]. Receiver operating characteristic analysis pointed to the utility of serum Klotho (area under the curve [AUC]: 0.817, 95% CI: 0.736-0.898, P < 0.001) and its gene expression in PBCs (AUC: 0.742, 95% CI: 0.647-0.836, P < 0.001) to distinguish subclinical atherosclerosis. The reductions in serum and PBCs expression levels of Klotho in CKD patients are independently associated with the presence of for subclinical atherosclerosis. Further research exploring whether therapeutic approaches to maintain or elevate Klotho could reduce the impact of CVD in CKD patients is warranted.
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Aterosclerose/diagnóstico , Glucuronidase/metabolismo , Insuficiência Renal Crônica/fisiopatologia , Idoso , Índice Tornozelo-Braço , Aterosclerose/metabolismo , Biomarcadores/sangue , Doenças Cardiovasculares/complicações , Espessura Intima-Media Carotídea , Estudos Transversais , Feminino , Expressão Gênica/genética , Glucuronidase/fisiologia , Humanos , Proteínas Klotho , Masculino , Pessoa de Meia-Idade , Curva ROC , Insuficiência Renal Crônica/complicações , Fatores de Risco , Índice de Gravidade de Doença , Espanha/epidemiologia , Transcriptoma/genéticaRESUMO
Observational studies have associated the increase in fibroblast growth factor (FGF) 23 levels, the main regulator of phosphate levels, with the onset of diabetes. These studies open the debate on the plausible existence of undescribed diabetogenic mechanisms derived from chronic supraphysiological levels of FGF23, a prevalent condition in chronic kidney disease (CKD) and end-stage renal disease (ESRD) patients. These maladaptive and diabetogenic responses to FGF23 may occur at different levels, including a direct effect on the pancreatic ß cells, and an indirect effect derived from the stimulation of the synthesis of pro-inflammatory factors. Both mechanisms could be mediated by the binding of FGF23 to noncanonical receptor complexes with the subsequent overactivation of signaling pathways that leads to harmful effects. The canonical binding of FGF23 to the receptor complex formed by the receptor FGFR1c and the coreceptor αKlotho activates Ras/MAPK/ERK signaling. However, supraphysiological concentrations of FGF23 favor non-αKlotho-dependent binding of this molecule to other FGFRs, which could generate an undesired overactivation of the PLCγ/CN/NFAT pathway, as observed in cardiomyocytes and hepatocytes. Moreover, the decrease in αKlotho expression may constitute a contributing factor to the appearance of these effects by promoting the nonspecific activation of the PLCγ/CN/NFAT to the detriment of the αKlotho-dependent Ras/MAPK/ERK pathway. The description of these mechanisms would allow the development of new therapeutic targets susceptible to be modified by dietary changes or by pharmacological intervention.
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BACKGROUND: Overhydration is a predictor of mortality in hemodialysis (HD) patients. Bioimpedance spectroscopy (BIS) is used to determine the body composition. Extracellular Water/Total Body Water (ECW/TBW) ratio has been proposed to predict mortality. METHODS: Multicenter, prospective, observational, proof-of-concept study to estimate the impact of ECW/TBW in global and cardiovascular mortality and the relationship with cardiovascular biomarkers. The study included 60 patients (mean age, 71.8 ± 11.4 years; mean time on HD, 52.3 ± 30.8 months) with a median follow-up of 30.5 months (IQ range, 17.2-34 months). RESULTS: Post-dialysis ECW/TBW was directly associated with NT-proBNP and cTnT. During the study 28 patients died, most of them (43%) due to cardiovascular events. Compared to the survivors, these subjects had a higher post-dialysis ECW/TBW ratio (p = 0.006), while for cardiovascular mortality the only significant difference was a higher pre-dialysis ECW/TBW. The ability of post-dialysis ECW/TBW ratio to predict all-cause mortality had an area under the ROC curve (AUC) of 0.71 (CI 95%, 0.57-0.81; p = 0.002), with a cutoff point of 0.5023. For cardiovascular mortality the AUC was 0.66 (CI 95%, 0.52-0.77; p = 0.045), with a cutoff point of 0.4713. CONCLUSIONS: The post-dialysis ECW/TBW ratio measured by BIS can be a predictor of all-cause and cardiovascular mortality.
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Água Corporal/fisiologia , Doenças Cardiovasculares/mortalidade , Impedância Elétrica , Espaço Extracelular/fisiologia , Diálise Renal , Desequilíbrio Hidroeletrolítico/diagnóstico , Idoso , Idoso de 80 Anos ou mais , Causas de Morte , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudo de Prova de Conceito , Estudos Prospectivos , Desequilíbrio Hidroeletrolítico/fisiopatologiaRESUMO
OBJECTIVE: Asymptomatic hyperuricaemia (AHU) is associated with inflammatory disorders, including cardiovascular disease. Uric acid (UA) lowering therapies may reduce the risk of appearance or the progression of these comorbidities. In this work, we investigated the relationship between serum UA levels and inflammation in subjects with AHU. METHODS: Serum levels of high-sensitivity CRP (hsCRP), TNF-α and IL-6, and mRNA expression of TNFa and IL6 in peripheral blood mononuclear cells were measured in individuals with AHU and without comorbid conditions and in a control group with similar characteristics and normal serum UA levels. Additionally, we determined the variations in the inflammatory profile in a subgroup of subjects after 6 months of treatment with allopurinol. RESULTS: Subjects at higher tertiles of serum UA presented higher levels of hsCRP and increased serum and mRNA expression levels of both cytokines (P < 0.001). UA levels constituted an independent predictor of increased levels of inflammatory parameters in multiple regression models (P < 0.001) and a risk factor for the presence of a subclinical inflammation in multivariate logistic regression (P < 0.001). Allopurinol reduced UA and serum and mRNA expression of inflammatory cytokines (P < 0.001). There was a significant correlation between the variations in serum UA and the variations in serum TNF-α (P < 0.01) and IL-6 (P < 0.05), and mRNA expression of these cytokines (P < 0.05). This association remained significant and independent (P < 0.01). CONCLUSION: In subjects with AHU, serum UA may be an inductor of subclinical inflammation. Therapeutic reduction of serum UA was associated with a modulation of the inflammatory profile.
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Proteína C-Reativa/metabolismo , Hiperuricemia/sangue , Inflamação/sangue , Interleucina-6/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Ácido Úrico/sangue , Feminino , Humanos , Hiperuricemia/complicações , Inflamação/complicações , Interleucina-6/sangue , Leucócitos Mononucleares/metabolismo , Masculino , Pessoa de Meia-Idade , Fator de Necrose Tumoral alfa/sangueRESUMO
One of the most frequent complications in patients with diabetes mellitus is diabetic nephropathy (DN). At present, it constitutes the first cause of end stage renal disease, and the main cause of cardiovascular morbidity and mortality in these patients. Therefore, it is clear that new strategies are required to delay the development and the progression of this pathology. This new approach should look beyond the control of traditional risk factors such as hyperglycemia and hypertension. Currently, inflammation has been recognized as one of the underlying processes involved in the development and progression of kidney disease in the diabetic population. Understanding the cascade of signals and mechanisms that trigger this maladaptive immune response, which eventually leads to the development of DN, is crucial. This knowledge will allow the identification of new targets and facilitate the design of innovative therapeutic strategies. In this review, we focus on the pathogenesis of proinflammatory molecules and mechanisms related to the development and progression of DN, and discuss the potential utility of new strategies based on agents that target inflammation.
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Decrease in soluble anti-aging Klotho protein levels is associated to cardiovascular disease (CVD). Diverse studies have shown a bidirectional relationship between Klotho and inflammation, a risk factor for the development of CVD. In this work we aimed to evaluate the association between Klotho and inflammatory cytokines levels in the context of human CVD.The study included 110 patients with established CVD and preserved renal function, and a control group of 22 individuals without previous history of cardiovascular events. Serum Klotho and IL10 levels were significantly lower in the CVD group. Inflammatory status, marked by the TNFα/IL10 ratio and the C-reactive protein (CRP) levels, was significantly increased in the group of patients with established CVD. Soluble Klotho levels were directly correlated with eGFR (r=0.217) and IL10 (r=0.209) and inversely correlated with age (r=-0.261), CRP (r=-0.203), and TNFα/IL10 (r=-0.219). This association with TNFα/IL10 remained significant in age-matched subgroups. Multiple logistic regression analysis showed that age, smoking and the neutrophil-to-lymphocyte ratio (NLR) constituted risk factors for the presence of CVD, while Klotho was a protective factor.In conclusion, in patients with established CVD, the reduction in soluble Klotho is associated with a pro-inflammatory status marked by lower IL10 concentrations and higher TNFα/IL10 ratio and CRP levels.
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Biomarcadores , Doenças Cardiovasculares/sangue , Citocinas/sangue , Glucuronidase/sangue , Mediadores da Inflamação/sangue , Idoso , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/terapia , Estudos de Casos e Controles , Comorbidade , Feminino , Humanos , Proteínas Klotho , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores de RiscoRESUMO
Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease and a main contributing factor for cardiovascular morbidity and mortality in patients with diabetes mellitus. Strategies employed to delay the progression of this pathology focus on the control of traditional risk factors, such as hyperglycemia, and elevated blood pressure. Although the intimate mechanisms involved in the onset and progression of DKD remain incompletely understood, inflammation is currently recognized as one of the main underlying processes. Untangling the mechanisms involved in the appearing of a harmful inflammatory response in the diabetic patient is crucial for the development of new therapeutic strategies. In this review, we focus on the inflammation-related pathogenic mechanisms involved in DKD and in the therapeutic utility of new anti-inflammatory strategies.
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Cerebrospinal fluid (CSF) free light chains (FLC) may be an alternative biomarker to oligoclonal bands (OCB) in multiple sclerosis (MS). Herein, we compared the diagnostic accuracy of CSF OCB and FLC and we tested the prognostic value of FLC in a cohort of 64 MS patients and 106 controls. A κ-index >7.83 was more sensitive but less specific than OCB in discriminating MS patients from controls. Additionally, a κ-index >10.61 performed better than OCB in the discrimination between MS and controls with inflammatory neurological diseases (pâ¯<â¯.001). In clinically isolated syndrome (CIS) patients, a κ-index >10.61 significantly predicted time to conversion to MS (pâ¯=â¯.020). κ-index might be a valid alternative to OCB as a diagnostic biomarker for MS and might also be a prognostic marker in CIS.
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Cadeias Leves de Imunoglobulina/líquido cefalorraquidiano , Esclerose Múltipla/líquido cefalorraquidiano , Esclerose Múltipla/diagnóstico , Bandas Oligoclonais/líquido cefalorraquidiano , Adulto , Idoso , Biomarcadores/líquido cefalorraquidiano , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Vascular calcification is a major risk for cardiovascular disease and implies the transformation of smooth muscle cells to an osteoblastic phenotype as a consequence of dysregulation of calcium and phosphate metabolism. Fibroblast growth factor (FGF) 23 is the most potent phosphate regulator. Observational studies suggest that high levels of FGF23 are related to cardiovascular morbidity and mortality. In this work, we determined the levels of both the intact and the carboxi-terminal fragments of circulating FGF23 in 133 patients with established cardiovascular disease, the expression of FGF23, its receptors 1 and 3, and its co-receptor Klotho in vascular fragments of aorta, carotid and femoral in 43 out of this group of patients, and in a control group of 20 organ donors. Patients with atherosclerosis and vascular calcification presented increased levels of FGF23 respect to the control group. Vascular immunoreactivity for FGF23 was also significantly increased in patients with vascular calcification as compared to patients without calcification and to controls. Finally, gene expression of FGF23 and RUNX2 were also higher and directly related in vascular samples with calcification. Conversely, expression of Klotho was reduced in patients with cardiovascular disease when comparing to controls. In conclusion, our findings link the calcification of the vascular tissue with the expression of FGF23 in the vessels and with the elevation of circulating levels this hormone.
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Aorta/metabolismo , Artérias Carótidas/metabolismo , Artéria Femoral/metabolismo , Fatores de Crescimento de Fibroblastos/metabolismo , Calcificação Vascular/metabolismo , Idoso , Aorta/patologia , Artérias Carótidas/patologia , Feminino , Artéria Femoral/patologia , Fator de Crescimento de Fibroblastos 23 , Glucuronidase , Humanos , Proteínas Klotho , Masculino , Pessoa de Meia-Idade , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Calcificação Vascular/patologiaRESUMO
BACKGROUND: Diabetic foot syndrome (DFS) is a prevalent complication in the diabetic population and a major cause of hospitalizations. Diverse clinical studies have related alterations in the system formed by fibroblast growth factor (FGF)-23 and Klotho (KL) with vascular damage. In this proof-of-concept study, we hypothesize that the levels of FGF23 and Klotho are altered in DFS patients. METHODS: Twenty patients with limb amputation due to DFS, 37 diabetic patients without DFS, and 12 non-diabetic cadaveric organ donors were included in the study. Serum FGF23/Klotho and inflammatory markers were measured by enzyme-linked immunosorbent assay (ELISA). Protein and gene expression levels in the vascular samples were determined by immunohistochemistry and quantitative real-time PCR, respectively. RESULTS: Serum Klotho is significantly reduced and FGF23 is significantly increased in patients with DFS (p < 0.01). Vascular immunoreactivity and gene expression levels for Klotho were decreased in patients with DFS (p < 0.01). Soluble Klotho was inversely related to serum C-reactive protein (r = -0.30, p < 0.05). Vascular immunoreactivities for Klotho and IL6 showed an inverse association (r = -0.29, p < 0.04). Similarly, vascular gene expression of KL and IL6 were inversely associated (r = -0.31, p < 0.05). Logistic regression analysis showed that higher Klotho serum concentrations and vascular gene expression levels were related to a lower risk of DFS, while higher serum FGF23 was associated with a higher risk for this complication. CONCLUSION: FGF23/Klotho system is associated with DFS, pointing to a new pathophysiological pathway involved in the development and progression of this complication.
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Diabetic kidney disease is one of the most relevant complications in diabetes mellitus patients, which constitutes the main cause of end-stage renal disease in the western world. Delaying the progression of this pathology requires new strategies that, in addition to the control of traditional risk factors (glycemia and blood pressure), specifically target the primary pathogenic mechanisms. Nowadays, inflammation is recognized as a critical novel pathogenic factor in the development and progression of renal injury in diabetes mellitus. Pentoxifylline is a nonspecific phosphodiesterase inhibitor with rheologic properties clinically used for more than 30 years in the treatment of peripheral vascular disease. In addition, this compound also exerts anti-inflammatory actions. In the context of diabetic kidney disease, pentoxifylline has shown significant antiproteinuric effects and a delay in the loss of estimated glomerular filtration rate, although at the present time there is no definitive evidence regarding renal outcomes. Moreover, recent studies have reported that this drug can be associated with a positive impact on new factors related to kidney health, such as Klotho. The use of pentoxifylline as renoprotective therapy for patients with diabetic kidney disease represents a new example of drug repositioning.
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OBJECTIVE: The effect of pentoxifylline on Klotho levels in patients with type 2 diabetes mellitus with chronic kidney disease (CKD) was assessed in a post hoc analysis of the Pentoxifylline for Renoprotection in Diabetic Nephropathy (PREDIAN) trial. RESEARCH DESIGN AND METHODS: Circulating and urinary tumor necrosis factor-α (TNF-α) and Klotho were measured before and after 1 year of pentoxifylline. The effect on Klotho expression was assessed in cultured renal tubular cells. RESULTS: Pentoxifylline administration resulted in decreased serum and urinary TNF-α, whereas serum and urinary Klotho increased significantly. Changes in urinary Klotho, urinary TNF-α, and phosphorus were associated with changes in serum Klotho; changes in estimated glomerular filtration rate, urinary TNF-α, and albuminuria were related to urinary Klotho variation. In renal tubular cells, pentoxifylline prevented the decrease in Klotho expression induced by inflammatory cytokines or albumin. CONCLUSIONS: Pentoxifylline increased Klotho levels in patients with diabetes with stage 3-4 CKD and prevented reduced Klotho expression in vitro. This beneficial effect may be related to anti-inflammatory and antialbuminuric activity.
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Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/urina , Nefropatias Diabéticas/sangue , Nefropatias Diabéticas/urina , Glucuronidase , Túbulos Renais/efeitos dos fármacos , Pentoxifilina/farmacologia , Adulto , Idoso , Albuminúria/sangue , Albuminúria/complicações , Albuminúria/urina , Animais , Células Cultivadas , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Nefropatias Diabéticas/tratamento farmacológico , Feminino , Seguimentos , Taxa de Filtração Glomerular/efeitos dos fármacos , Glucuronidase/sangue , Glucuronidase/urina , Humanos , Rim/efeitos dos fármacos , Rim/metabolismo , Túbulos Renais/metabolismo , Proteínas Klotho , Masculino , Camundongos , Pessoa de Meia-Idade , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/urina , Fator de Necrose Tumoral alfa/metabolismo , Fator de Necrose Tumoral alfa/urinaRESUMO
Atherosclerosis is a chronic inflammatory disorder affecting the artery wall. Klotho, an anti-aging factor expressed in the vessel walls that participates in the maintenance of vascular homeostasis, can be down-regulated by inflammation. In this proof-of-concept work we seek to characterize the arterial KLOTHO expression in the vascular wall, as well as the serum concentration of this protein, in a group of patients with clinical atherosclerotic disease. In addition, we aim to analyze the relationship between Klotho and inflammation. Vascular samples were obtained from 27 patients with atherosclerotic disease under an elective vascular surgery procedure, and from 11 control subjects (cadaveric organ donation programme). qRT-PCR was performed to analyze the gene expression of KLOTHO, TNF-α, IL-6, and IL-10 Serum levels of soluble KLOTHO were measured by ELISA. As compared with control subjects, serum concentrations and vascular expression of Klotho were lower in patients with atherosclerotic vascular disease, whereas inflammatory status was significantly higher. There was a negative and significant correlation between inflammatory parameters and Klotho. After controlling for the effect of other variables, partial correlation showed a direct relationship between vascular KLOTHO gene expression and IL-10 mRNA levels, whereas there was a negative association with serum LDL concentrations and vascular TNF-α expression. Our study indicates an inverse interrelationship between inflammation and Klotho in atherosclerosis. Further studies are necessary to elucidate whether the inflammatory state causes Klotho deficiency or, on the contrary, reduction of Klotho could be responsible for greater inflammation, and finally, to investigate the potential clinical relevance of this association.
Assuntos
Aterosclerose/genética , Aterosclerose/metabolismo , Expressão Gênica/fisiologia , Glucuronidase/metabolismo , Inflamação/metabolismo , Feminino , Fatores de Crescimento de Fibroblastos/genética , Fatores de Crescimento de Fibroblastos/metabolismo , Glucuronidase/deficiência , Glucuronidase/genética , Humanos , Inflamação/genética , Interleucina-10/sangue , Proteínas Klotho , Masculino , Insuficiência Renal Crônica/sangue , Solubilidade , Fator de Necrose Tumoral alfa/sangueRESUMO
BACKGROUND AND OBJECTIVES: Paricalcitol, a selective vitamin D receptor activator, is used to treat secondary hyperparathyroidism in kidney transplant patients. Experimental and clinical studies in non-transplant kidney disease patients have found this molecule to have anti-inflammatory properties. In this exploratory study, we evaluated the anti-inflammatory profile of paricalcitol in kidney-transplant recipients. METHODS: Thirty one kidney transplant recipients with secondary hyperparathyroidism completed 3 months of treatment with oral paricalcitol (1µg/day). Serum concentrations and gene expression levels of inflammatory cytokines in peripheral blood mononuclear cells were analysed at the beginning and end of the study. RESULTS: Paricalcitol significantly decreased parathyroid hormone levels with no changes in calcium and phosphorous. It also reduced serum concentrations of interleukin (IL)-6 and tumour necrosis factor-alpha (TNF-α) by 29% (P<0.05) and 9.5% (P<0.05) compared to baseline, respectively. Furthermore, gene expression levels of IL-6 and TNF-α in peripheral blood mononuclear cells decreased by 14.1% (P<0.001) and 34.1% (P<0.001), respectively. The ratios between pro-inflammatory cytokines (TNF-α and IL-6) and anti-inflammatory cytokines (IL-10), both regarding serum concentrations and gene expression, also experienced a significant reduction. CONCLUSIONS: Paricalcitol administration to kidney transplant recipients has been found to have beneficial effects on inflammation, which may be associated with potential clinical benefits.
Assuntos
Anti-Inflamatórios/uso terapêutico , Citocinas/sangue , Ergocalciferóis/uso terapêutico , Hiperparatireoidismo Secundário/tratamento farmacológico , Transplante de Rim , Complicações Pós-Operatórias/tratamento farmacológico , Adulto , Idoso , Anti-Inflamatórios/farmacologia , Proteína C-Reativa/análise , Citocinas/biossíntese , Citocinas/genética , Ergocalciferóis/farmacologia , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Hiperparatireoidismo Secundário/sangue , Hiperparatireoidismo Secundário/etiologia , Inflamação , Leucócitos Mononucleares/metabolismo , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/etiologia , Estudos Prospectivos , Receptores de Calcitriol/agonistasRESUMO
The increase in the incidence of Alzheimer's disease (AD) in old women may be attributable to estrogen deficiency, and estrogen replacement therapy may be useful in preventing or delaying the onset of this disease. In neuronal membranes, 17 beta-estradiol interacts with estrogen receptors (mERs) located in lipid raft signalosomes which trigger neuroprotective responses by anchoring to scaffolding caveolin-1 complexed with other proteins. We suggest that mER-signalosome malfunctions in AD and by menopause due to development of aberrations in these microstructures. Here, we report that mER dissociates from a voltage-dependent anion channel (VDAC), and that progressive dephosphorylation of VDAC1 enhances neurotoxicity. mER dissociates from caveolin-1 and other neuroprotective proteins, including insulin-like growth factor 1 receptor beta. Similar signalosome disarrangements are observed in AD patients. Moreover, in AD, lipid rafts exhibit alterations in lipid composition, and these changes cause an increase in liquid-ordered as compared to controls. Together, the data show that AD and menopause lead to disruption in the lipid raft structure, and disfunctioning of ER alpha and other neuroprotectors integrated into these signalosomes.
Assuntos
Doença de Alzheimer/metabolismo , Receptor alfa de Estrogênio/metabolismo , Microdomínios da Membrana/metabolismo , Menopausa/metabolismo , Idoso , Caveolina 1 , Feminino , Lobo Frontal/metabolismo , Humanos , Pessoa de Meia-Idade , Fosforilação , Canal de Ânion 1 Dependente de Voltagem/metabolismoRESUMO
INTRODUCTION: In current study, we compared the accuracy of the PSA isoform p2PSA and its derivatives, the percentage of p2PSA to free PSA (%p2PSA) and the Prostate Health Index (PHI) in the detection of prostate cancer (PC) characteristics at the xFB01;nal pathology with respect to reference standards. MATERIALS AND METHODS: This was an observational prospective study evaluating 43 consecutive PC patients treated with laparoscopic/robotic radical prostatectomy (RP). Logistic regression models were fitted to test the predictors of pT3 stage, pathologic Gleason score ≥ 8 or Gleason score upgrading, margin status, lymph node invasion, and the presence of high-risk disease (pT3 disease and/or Gleason score ≥ 8 and/or positive lymph node). The comparative base model included tPSA, clinical stage, biopsy Gleason score, and percentage of positive core. RESULTS: Seventeen patients (39.5%) were affected by pT3 disease or had a pathologic Gleason score ≥ 8; positive margins were detected in 12 patients (27.9%), lymph node invasion was found in 2 patients (4.7%), and 15 patients (34.8%) harbored high-risk disease. In the univariate analysis, p2PSA, %p2PSA, and PHI were significant predictors of pT3 disease, pathologic Gleason score, and the presence of high-risk disease (all p < 0.05), whereas only PHI was an independent predictor of pT3 disease, margin status, and presence of high-risk disease, increasing the accuracy of a base multivariable model by 6.3% (p < 0.05) and 4.2% (p < 0.05) for the prediction of pT3 and high-risk disease, respectively. CONCLUSIONS: p2PSA and its derivatives, primarily PHI, were significant predictors of unfavorable PC characteristics as detected at the xFB01;nal pathology, thus improving the clinical performance of standard prognostic factors for aggressive disease.