Circulating and renal activity of angiotensin-converting enzyme 2 (ACE2) is increased in non-obese diabetic (NOD) mice. Because paricalcitol has been reported to protect against diabetic nephropathy, ...we investigated the role of paricalcitol in modulating ACE2 in these mice. In addition, renal ADAM17, a metalloprotease implied in ACE2 shedding, was assessed. NOD female and non-diabetic control mice were studied for 21 days after diabetes onset and divided into various treatment groups. Diabetic animals received either vehicle; 0.4 or 0.8 μg/kg paricalcitol, aliskiren, or a combination of paricalcitol and aliskiren. We then studied the effect of paricalcitol on ACE2 expression in proximal tubular epithelial cells. Paricalcitol alone or in combination with aliskiren resulted in significantly reduced circulating ACE2 activity in NOD mice but there were no changes in urinary albumin excretion. Serum renin activity was significantly decreased in mice that received aliskiren but no effect was found when paricalcitol was used alone. Renal content of ADAM17 was significantly decreased in animals that received a high dose of paricalcitol. Renal and circulating oxidative stress (quantified by plasma H2O2 levels and immunolocalization of nitrotyrosine) were reduced in high-dose paricalcitol-treated mice compared with non-treated diabetic mice. In culture, paricalcitol incubation resulted in a significant increase in ACE2 expression compared with nontreated cells. In NOD mice with type 1 diabetes, paricalcitol modulates ACE2 activity, ADAM17, and oxidative stress renal content independently from the glycemic profile and urinary albumin excretion. In tubular cells, paricalcitol may modulate ACE2 by blocking its shedding. In the early stage of diabetic nephropathy, paricalcitol treatment counterbalances the effect of diabetes on circulating ACE2 activity. Our results suggest that additional use of paricalcitol may be beneficial in treating patients with diabetes under standard therapeutic strategies.
Renin-angiotensin system within the diabetic podocyte Márquez, Eva; Riera, Marta; Pascual, Julio ...
American journal of physiology. Renal physiology,
2015-Jan-01, 2015-01-01, 20150101, Letnik:
308, Številka:
1
Journal Article
Recenzirano
Diabetic kidney disease is the leading cause of end-stage renal disease. Podocytes are differentiated cells necessary for the development and maintenance of the glomerular basement membrane and the ...capillary tufts, as well as the function of the glomerular filtration barrier. The epithelial glomerular cells express a local renin-angiotensin system (RAS) that varies in different pathological situations such as hyperglycemia or mechanical stress. RAS components have been shown to be altered in diabetic podocytopathy, and their modulation may modify diabetic nephropathy progression. Podocytes are a direct target for angiotensin II-mediated injury by altered expression and distribution of podocyte proteins. Furthermore, angiotensin II promotes podocyte injury indirectly by inducing cellular hypertrophy, increased apoptosis, and changes in the anionic charge of the glomerular basement membrane, among other effects. RAS blockade has been shown to decrease the level of proteinuria and delay the progression of chronic kidney disease. This review summarizes the local intraglomerular RAS and its imbalance in diabetic podocytopathy. A better understanding of the intrapodocyte RAS might provide a new approach for diabetic kidney disease treatment.
Zinc is an essential micronutrient that impacts host-pathogen interplay at infection. Zinc balances immune responses, and also has a proven direct antiviral action against some viruses. Importantly, ...zinc deficiency (ZD) is a common condition in elderly and individuals with chronic diseases, two groups with an increased risk for severe severe coronavirus disease 2019 (COVID-19) outcomes. We hypothesize that serum zinc content (SZC) influences COVID-19 disease progression, and thus might represent a useful biomarker.
We ran an observational cohort study with 249 COVID-19 patients admitted in Hospital del Mar. We have studied COVID-19 severity and progression attending to SZC at admission. In parallel, we have studied severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) replication in the Vero E6 cell line modifying zinc concentrations.
Our study demonstrates a correlation between serum zinc levels and COVID-19 outcome. Serum zinc levels lower than 50 µg/dL at admission correlated with worse clinical presentation, longer time to reach stability, and higher mortality. Our in vitro results indicate that low zinc levels favor viral expansion in SARS-CoV-2 infected cells.
Low SZC is a risk factor that determines COVID-19 outcome. We encourage performing randomized clinical trials to study zinc supplementation as potential prophylaxis and treatment with people at risk of zinc deficiency.
Headache is among the most frequent symptoms of acute COVID-19 infection. Its mechanisms remain obscure, but due to its migraine-like characteristics, the activation of the trigeminal system could ...account for its underlying pathophysiology.
Our aim was to compare the serum levels of CGRP, as a theoretical marker of trigemino-vascular activation, in 25 COVID-19 inpatients with lung involvement experiencing headache, against 15 COVID-19 inpatients without headache and with those of 25 matched healthy controls with no headache history.
Morning serum alpha-CGRP levels, as measured by ELISA (Abbexa, UK), were increased in COVID-19 patients with headache (55.2±34.3 pg/mL) vs. controls (33.9±14.0 pg/mL) (p < 0.01). Alpha-CGRP levels in COVID-19 patients without headache were also significantly increased (43.3 ± 12.8 pg/mL; p = 0.05) versus healthy controls, but were numerically lower (-28.2%; p = 0.36) as compared to COVID-19 patients with headache.
CGRP levels are increased in COVID-19 patients experiencing headache in the acute phase of this disease, which could explain why headache frequently occurs in COVID-19 and strongly supports a role for trigeminal activation in the pathophysiology of headache in this viral infection.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
This paper proposes an energy management strategy for a residential electrothermal microgrid, based on renewable energy sources. While grid connected, it makes use of a hybrid electrothermal storage ...system, formed by a battery and a hot water tank along with an electrical water heater as a controllable load, which make possible the energy management within the microgrid. The microgrid emulates the operation of a single family home with domestic hot water (DHW) consumption, a heating, ventilation and air conditioning (HVAC) system as well as the typical electric loads. An energy management strategy has been designed which optimizes the power exchanged with the grid profile in terms of peaks and fluctuations, in applications with high penetration levels of renewables. The proposed energy management strategy has been evaluated and validated experimentally in a full scale residential microgrid built in our Renewable Energy Laboratory, by means of continuous operation under real conditions. The results show that the combination of electric and thermal storage systems with controllable loads is a promising technology that could maximize the penetration level of renewable energies in the electric system.
La hipertensión arterial resistente (HTAR) supone un importante impacto a nivel multiorgánico e incrementa la morbimortalidad. Este trabajo evalúa la evolución de la lesión orgánica mediada por ...hipertensión en pacientes con HTAR tras añadir espironolactona.
Estudio retrospectivo de 58 pacientes con HTAR a quienes se añadió espironolactona (12,5-25mg/día). Se obtuvieron parámetros de presión arterial clínica y MAPA-24h, cociente albúmina/creatinina y datos ecocardiográficos previos a iniciar espironolactona y tras 12 meses de tratamiento.
El 36,2% de los pacientes eran mujeres y la edad media de 67,3±10,1 años. Se objetivó un descenso en albuminuria (mediana RIC25-75) de 27,0 (7,5-255,4) a 11,3 (3,1-37,8) mg/g (p = 0,009), siendo más marcado en pacientes con albuminuria grado A2 y A3: de 371,2 (139,5-797,4) a 68,4 (26,5-186,5) mg/g, p =0,02.. A nivel ecocardiográfico se evidenció: pared posterior: −1,0±0,4mm (p<0,001), tabique interventricular: −0,6±0,5mm (p=0,01), índice de masa del ventrículo izquierdo (VI): −14,7±10,2g/m2 (p=0,006), índice de remodelado del VI: −0,04±0,036 (p=0,03), sin cambios estadísticamente significativos en fracción de eyección VI, diámetro diastólico VI, diámetro sistólico VI, diámetro de aurícula izquierda, relación entre onda de llenado ventricular temprano y contracción auricular ni en índice de presión llenado VI.
La presión arterial clínica sistólica/diastólica presentó un descenso de −12,5±4,9/−4,9±3,0mmHg, p<0,001. En los MAPA-24h se observó un descenso significativo de presión arterial sistólica y diastólica en los períodos diurno y nocturno, y un cambio favorable en el patrón circadiano en el 38,1% de los pacientes, p<0,001.
Añadir espironolactona en HTAR contribuye a la reducción de la lesión orgánica mediada por hipertensión a nivel de albuminuria y de parámetros ecocardiográficos de cardiopatía hipertensiva.
Resistant hypertension (RH) represents an important multi-organic impact and increases the morbi-mortality. We aimed to evaluate the evolution of hypertensive mediated organ damage in patients with RH after adding spironolactone.
Retrospective study of 58 patients with RH who started spironolactone (12.5–25mg daily). Office blood pressure, 24-h ambulatory blood pressure monitoring (24h-ABPM), urine albumin-to-creatinine ratio and echocardiographic parameters were analyzed prior to initiation of spironolactone and after 12 months of treatment.
Thirty-six percent of patients were women and mean age was 67.3±10.1 years. We observed a decrease in urine albumin-to-creatinine ratio (median RIQ25–75) of 27.0 (7.5-255.4) to 11.3 (3.1–37.8) mg/g, P = .009. This was more relevant in patients with albuminuria grade A2 and A3: 371.2 (139.5–797.4) to 68.4 (26.5–186.5) mg/g, P = .02. The echocardiographic changes were: posterior wall thickness: −1.0±0.4mm (P<.001), interventricular septal thickness: −0.6±0.5mm (P=.01), left ventricular (LV) mass index: −14.7±10.2g/m2 (P=.006), LV remodeling index: −0.04±0.036 (P=.03), without statistically significant changes in LV ejection fraction, LV end-diastolic diameter, LV end-systolic diameter, left atrial diameter, relationship between early ventricular filling wave and atrial contraction and LV filling pressure index.
Systolic/diastolic office blood pressure decreased −12.5±4.9/−4.9±3.0mmHg, P<.001. In 24h-ABPM, systolic and diastolic BP had a significant decrease in diurnal and nocturnal periods and 38.1% of patients presented a favorable change in the circadian pattern, P<.001.
Adding spironolactone to patients with RH contributes to improve hypertensive mediated organ damage by reducing albuminuria levels and echocardiographic parameters of hypertensive heart disease.
Immunosuppressive drugs are widely used to prevent rejection after kidney transplantation. However, the pharmacological response to a given immunosuppressant can vary markedly between individuals, ...with some showing poor treatment responses and/or experiencing serious side effects. There is an unmet need for diagnostic tools that allow clinicians to individually tailor immunosuppressive therapy to a patient's immunological profile. The Immunobiogram (IMBG) is a novel blood-based in vitro diagnostic test that provides a pharmacodynamic readout of the immune response of individual patients to a range of immunosuppressants commonly used in kidney transplant recipients. Here, we discuss the current approaches used to measure the pharmacodynamic responses of individual patients to specific immunosuppressive drugs in vitro, which can then be correlated with patient's clinical outcomes. We also describe the procedure of the IMBG assay, and summarize the results obtained using the IMBG in different kidney transplant populations. Finally, we outline future directions and other novel applications of the IMBG, both in kidney transplant patients and other autoimmune diseases.
Background
Calcitonin gene-related peptide (CGRP) is the most promising candidate to become the first migraine biomarker. However, literature shows clashing results and suggests a methodological ...source for such discrepancies. We aimed to investigate some of these methodological factors to evaluate the actual role of CGRP as biomarker.
Methods
Previous to the experimental part, we performed a literature review of articles measuring CGRP in migraine patients. Using our 399 bio-bank sera samples, we performed a series of experiments to test the validity of different ELISA kits employed, time of sample processing, long-term storage, sampling in rest or after moderate exercise. Analysis of in-house data was performed to analyse average levels of the peptide and the effect of sex and age.
Results
Literature review shows the high variability in terms of study design, determination methods, results and conclusions obtained by studies including CGRP determinations in migraine patients. CGRP measurements depends on the method and specific kit employed, also on the isoform detected, showing completely different ranges of concentrations. Alpha-CGRP and beta-CGRP had median with IQR levels of 37.5 (28.2–54.4) and 4.6 (2.4–6.4)pg/mL, respectively. CGRP content is preserved in serum within the 24 first hours when samples are stored at 4°C after clotting and immediate centrifugation. Storages at -80°C of more than 6 months result in a decrease in CGRP levels. Moderate exercise prior to blood extraction does not modulate the concentration of the peptide. Age positively correlates with beta-CGRP content and men have higher alpha-CGRP levels than women.
Conclusions
We present valuable information for CGRP measurements in serum. ELISA kit suitability should be tested prior to the experiments. Alpha and beta-CGRP levels should be analysed separately as they can show different behaviours even within the same condition. Samples can be processed in a 24-h window if they have been kept in 4°C and should not be stored for more than 6 months at -80°C before assayed. Patients do not need to rest before the blood extraction unless they have performed a high-endurance exercise. For comparative studies, sex and age should be accounted for as these parameters can impact CGRP concentrations.
Graphical Abstract
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