Moderate Antiproteinuric Effect of Add-On Aldosterone Blockade with Eplerenone in Non-Diabetic Chronic Kidney Disease. A Randomized Cross-Over Study

Reduction of proteinuria and blood pressure (BP) with blockers of the renin-angiotensin system (RAS) impairs the progression of chronic kidney disease (CKD). The aldosterone antagonist spironolactone has an antiproteinuric effect, but its use is limited by side effects. The present study evaluated the short-term antiproteinuric effect and safety of the selective aldosterone antagonist eplerenone in non-diabetic CKD.Open randomized cross-over trial.Forty patients with non-diabetic CKD and urinary albumin excretion greater than 300 mg/24 hours.Eight weeks of once-daily administration of add-on 25–50 mg eplerenone to stable standard antihypertensive treatment including RAS-blockade.24 hour urinary albumin excretion, BP, p-potassium, and creatinine clearance.The mean urinary albumin excretion was 22% [CI: 14,28], P<0.001, lower during treatment with eplerenone. Mean systolic BP was 4 mmHg [CI: 2,6], P = 0.002, diastolic BP was 2 mmHg [CI: 0,4], P = 0.02, creatinine clearance was 5% [CI: 2,8], P = 0.005, lower during eplerenone treatment. After correction for BP and creatinine clearance differences between the study periods, the mean urinary albumin excretion was 14% [CI: 4,24], P = 0.008 lower during treatment. Mean p-potassium was 0.1 mEq/L [CI: 0.1,0.2] higher during eplerenone treatment, P<0.001. Eplerenone was thus well tolerated and no patients were withdrawn due to hyperkalaemia.Open label, no wash-out period and a moderate sample size.In non-diabetic CKD patients, the addition of eplerenone to standard antihypertensive treatment including RAS-blockade caused a moderate BP independent fall in albuminuria, a minor fall in creatinine clearance and a 0.1 mEq/L increase in p-potassium

Sustained hyperosmolarity increses TGF-beta1 and Egr-1 expression in the rat renal medulla.

BACKGROUND: Although TGF-ss and the transcription factor Egr-1 play an important role in both kidney fibrosis and in response to acute changes of renal medullary osmolarity, their role under sustained hypo- or hyperosmolar conditions has not been elucidated. We investigated the effects of chronic hypertonicity and hypotonicity on the renal medullary TGF-ss and Egr-1 expression. METHODS: Male adult Sprague Dawley rats (n = 6/group) were treated with 15 mg/day furosemide, or the rats were water restricted to 15 ml/200 g body weight per day. Control rats had free access to water and rodent chow. Kidneys were harvested after 5 days of treament. In cultured inner medullary collecting duct (IMCD) cells, osmolarity was increased from 330 mOsm to 900 mOsm over 6 days. Analyses were performed at 330, 600 and 900 mOsm. RESULTS: Urine osmolarity has not changed due to furosemide treatment but increased 2-fold after water restriction (p < 0.05). Gene expression of TGF-ss and Egr-1 increased by 1.9-fold and 7-fold in the hypertonic medulla, respectively (p < 0.05), accompanied by 6-fold and 2-fold increased c-Fos and TIMP-1 expression, respectively (p < 0.05) and positive immunostaining for TGF-ss and Egr-1 (p < 0.05). Similarly, hyperosmolarity led to overexpression of TGF-ss and Egr-1 mRNA in IMCD cells (2.5-fold and 3.5-fold increase from 330 to 900 mOsm, respectively (p < 0.05)) accompanied by significant c-Fos and c-Jun overexpressions (p < 0.01), and increased Col3a1 and Col4a1 mRNA expression. CONCLUSION: We conclude that both TGF-ss and Egr-1 are upregulated by sustained hyperosmolarity in the rat renal medulla, and it favors the expression of extracellular matrix components

NFAT5 Is Activated by Hypoxia: Role in Ischemia and Reperfusion in the Rat Kidney

The current hypothesis postulates that NFAT5 activation in the kidney's inner medulla is due to hypertonicity, resulting in cell protection. Additionally, the renal medulla is hypoxic (10–18 mmHg); however there is no information about the effect of hypoxia on NFAT5. Using in vivo and in vitro models, we evaluated the effect of reducing the partial pressure of oxygen (PO2) on NFAT5 activity. We found that 1) Anoxia increased NFAT5 expression and nuclear translocation in primary cultures of IMCD cells from rat kidney. 2) Anoxia increased transcriptional activity and nuclear translocation of NFAT5 in HEK293 cells. 3) The dose-response curve demonstrated that HIF-1α peaked at 2.5% and NFAT5 at 1% of O2. 4) At 2.5% of O2, the time-course curve of hypoxia demonstrated earlier induction of HIF-1α gene expression than NFAT5. 5) siRNA knockdown of NFAT5 increased the hypoxia-induced cell death. 6) siRNA knockdown of HIF-1α did not affect the NFAT5 induction by hypoxia. Additionally, HIF-1α was still induced by hypoxia even when NFAT5 was knocked down. 7) NFAT5 and HIF-1α expression were increased in kidney (cortex and medulla) from rats subjected to an experimental model of ischemia and reperfusion (I/R). 7) Experimental I/R increased the NFAT5-target gene aldose reductase (AR). 8) NFAT5 activators (ATM and PI3K) were induced in vitro (HEK293 cells) and in vivo (I/R kidneys) with the same timing of NFAT5. 8) Wortmannin, which inhibits ATM and PI3K, reduces hypoxia-induced NFAT5 transcriptional activation in HEK293 cells. These results demonstrate for the first time that NFAT5 is induced by hypoxia and could be a protective factor against ischemic damage

Why are mineralocorticoid receptor antagonists cardioprotective?

Two clinical trials, the Randomized ALdosterone Evaluation Study (RALES) and the EPlerenone HEart failure and SUrvival Study (EPHESUS), have recently shown that mineralocorticoid receptor (MR) antagonists reduce mortality in patients with heart failure on top of ACE inhibition. This effect could not be attributed solely to blockade of the renal MR-mediated effects on blood pressure, and it has therefore been proposed that aldosterone, the endogenous MR agonist, also acts extrarenally, in particular in the heart. Indeed, MR are present in cardiac tissue, and possibly aldosterone synthesis occurs in the heart. This review critically addresses the following questions: (1) is aldosterone synthesized at cardiac tissue sites, (2) what agonist stimulates cardiac MR normally, and (3) what effects are mediated by aldosterone/MR in the heart that could explain the beneficial effects of MR blockade in heart failure? Conclusions are that most, if not all, of cardiac aldosterone originates in the circulation (i.e., is of adrenal origin), and that glucocorticoids, in addition to aldosterone, may serve as the endogenous agonist of cardiac MR. MR-mediated effects in the heart include effects on endothelial function, cardiac fibrosis and hypertrophy, oxidative stress, cardiac inotropy, coronary flow, and arrhythmias. Some of these effects occur via or in synergy with angiotensin II, and involve a non-MR-mediated mechanism. This raises the possibility that aldosterone synthase inhibitors might exert beneficial effects on top of MR blockade

Вплив забруднення атмосферного частинок і метеорологічних параметрів на закритих дрібних рівнів частинок в двох різних системах вентиляції

The results show that the relationships vary predominantly with particles size range and the air exchange rate. The influence seems to be lower with the M-SOV system due to the air filtration, the pressurization effect and the high air exchange rate.  Keywords: Supply-only ventilation, Extract-only ventilation, fine particles, indoor/outdoor relationship, experimental study.Результаты показывают, что отношения преимущественно меняться в зависимости от диапазона размера частиц и скорости воздухообмена. Влияние, как представляется, ниже, с системой M-SOV за счет фильтрации воздуха, эффект повышения давления и валютного курса с высокой воздухопроницаемостью. Ключевые слова: Поставка только вентиляция, приточно-только вентиляция, мелкие частицы, внутри / вне помещений отношения, экспериментальное исследование.Результати показують, що відносини переважно змінюватися в залежності від діапазону розміру часток і швидкості повітрообміну. Вплив, як видається, нижче, з системою M-SOV за рахунок фільтрації повітря, ефект підвищення тиску і валютного курсу з високою повітропроникністю. Ключові слова: Поставка тільки вентиляція, приточно-тільки вентиляція, дрібні частинки, всередині / поза приміщеннями відносини, експериментальне дослідження

Cambios fisiológicos asociados al envejecimiento

La población envejece en forma acelerada, y la comprensión de los cambios fisiológicos asociados al envejecimiento es una herramienta importante para enfrentar las demandas biomédicas y sociales de ese grupo etario. El objetivo de la presente revisión es definir los principales cambios morfológicos y funcionales en los sistemas cardiovascular, renal, nervioso central, muscular y metabolismo de la glucosa asociados a la edad. La evidencia de estudios clínicos y experimentales muestra que el envejecimiento de los vasos sanguíneos y el corazón se asocia a la pérdida de células musculares y menor distensibilidad. La fracción de eyección se mantiene constante. El riñón muestra disminución moderada de la velocidad de filtración glomerular, esclerosis vascular y glomerular, menor capacidad de concentración/dilución y de hidroxilación de la vitamina D. El cerebro disminuye su volumen, pero no por una pérdida generalizada de neuronas ni de arborización dendrítica. Hay menor capacidad de atención, memoria de trabajo y trastornos motores. La masa muscular disminuye y aumenta su infiltración grasa, asociado a disminución progresiva de la fuerza. El aumento de grasa corporal, especialmente visceral, participaría en una mayor resistencia insulínica que asociada a la disminución de la masa de células beta facilitaría el desarrollo de diabetes. La evidencia disponible muestra importantes cambios morfológicos y funcionales asociados a la edad. El conocimiento de la población en edad media de la vida no debiera generalizarse a los adultos mayores. El reconocimiento de cambios debidos al envejecimiento normal es difícil por la gran variabilidad entre sujetos y la alta prevalencia de comorbilidad