ABSTRACT
BACKGROUND: Angiotensin receptor 1 blockers (ARB) are standard nephroprotective drugs in chronic kidney disease. There is less evidence for a nephroprotective effect of HMG-CoA reductase inhibitors (statins) and much less is known about potential benefits of combination therapy. We evaluated the therapeutic potential of a statin alone or in combination with an ARB in experimental chronic kidney disease. METHODS: Subtotally nephrectomized (5/6 Nx) rats were treated early with vehicle, losartan, cerivastatin or losartan/cerivastatin. Expression of messenger RNA (mRNA) was assessed by real-time reverse transcription-polymerase chain reaction. Tissue proteins were localized by immunohistochemistry. Nuclear factor-κB (NF-κB) activation was measured in whole kidneys. RESULTS: In contrast to the sham group, at 6 weeks, vehicle-treated 5/6 Nx rats displayed renal lesions, albuminuria and increased blood pressure, serum creatinine and total kidney NF-κB p65 DNA-binding activity and preproendothelin-1, fibronectin and type I and III collagen mRNA. NF-κB activation correlated with albuminuria and histological renal injury. Losartan or combination therapy preserved renal function, abrogated albuminuria and improved glomerular and interstitial histology. Cerivastatin alone preserved renal function and improved interstitial injury but did not influence albuminuria, glomerular histology or NF-κB activation. Losartan/cerivastatin normalized kidney NF-κB activation and extracellular matrix mRNA expression pattern. The effect of losartan alone on these parameters was less intense. All treatments decreased preproendothelin-1 mRNA and preserved interstitial capillaries. CONCLUSIONS: In a chronic kidney disease model, early treatment with either an ARB or a statin preserved renal function although the mechanisms differed. Combination therapy with an ARB and a statin did not confer clear-cut advantages on biochemical and histological parameters over ARB alone, although it further improved the kidney NF-κB and gene expression profile.
Subject(s)
Angiotensin Receptor Antagonists/therapeutic use , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Kidney Diseases/etiology , Kidney Diseases/prevention & control , Losartan/therapeutic use , Nephrectomy/adverse effects , Pyridines/therapeutic use , Angiotensin II Type 1 Receptor Blockers/antagonists & inhibitors , Animals , Blotting, Western , Collagen Type I/genetics , Collagen Type I/metabolism , Collagen Type III/genetics , Collagen Type III/metabolism , Drug Therapy, Combination , Fibronectins/genetics , Fibronectins/metabolism , Kidney Diseases/pathology , Male , NF-kappa B/genetics , NF-kappa B/metabolism , RNA, Messenger/genetics , Rats , Rats, Sprague-Dawley , Real-Time Polymerase Chain Reaction , Reverse Transcriptase Polymerase Chain ReactionABSTRACT
We evaluated the anti-hypertensive and anti-albuminuric effect of the angiotensin receptor blocker telmisartan alone and in combination with torasemide and amlodipine. Patients were hypertensive, both diabetics and non-diabetics with persistent microalbuminuria. Our primary endpoint was a change in microalbuminuria levels, while the secondary endpoints were changes in systolic blood pressure (SBP), diastolic blood pressure (DBP), serum creatinine levels, and glomerular filtration rate.After the 16-week treatment period, the patients significantly reduced microalbuminuria levels (76.4 ± 52.4 µg/min; p < 0.001), SBP (16.4 ± 8.7 mmHg; p < 0.001) and DBP (17.7 ± 5.9 mmHg; p < 0.001). Both diabetics and non-diabetics showed an identical pattern of significance with respect to the whole population. Systolic blood pressure, DBP, and microalbuminuria were significantly reduced as a consequence of therapy, both in diabetics and non-diabetics.
Subject(s)
Albuminuria/drug therapy , Angiotensin II Type 1 Receptor Blockers/administration & dosage , Benzimidazoles/administration & dosage , Benzoates/administration & dosage , Hypertension, Renal/drug therapy , Adult , Aged , Aged, 80 and over , Amlodipine/administration & dosage , Antihypertensive Agents/administration & dosage , Blood Pressure/drug effects , Creatinine/blood , Diabetic Nephropathies/drug therapy , Drug Therapy, Combination , Female , Glomerular Filtration Rate/drug effects , Humans , Male , Middle Aged , Prospective Studies , Sulfonamides/administration & dosage , Telmisartan , Torsemide , Treatment OutcomeABSTRACT
INTRODUCTION AND OBJECTIVES: Previous studies angiotensin-converting enzyme gene insertion/deletion polymorphism ACE (I/D), angiotensinogen gene polymorphism, and angiotensin II AT1 receptor polymorphism in relation to coronary heart disease controversial results. This study was designed to analyze the association between these gene polymorphisms and the first coronary event in individuals residing on Grand Canary Island, Spain. PATIENTS AND METHOD: Case-control study. Case subjects (n = 304) were recruited at the first coronary event; age-matched controls (n = 315) were randomly selected from the Grand Canary population. Participants were examined for the usual risk factors. Blood samples were obtained for biochemical analyses and DNA extraction. Genotyping was performed by PCR and restriction analysis. RESULTS: Neither ACE (I/D) nor AT1 receptor polymorphism was associated with coronary heart disease, whereas the frequency distribution of AGT M235T genotypes among patients and control subjects (TT: 29% and 19%; MT: 48% and 50%; MM: 22% and 31%, respectively) was statistically different (p = 0.003). Multiple logistic regression analysis identified the TT genotype of the angiotensinogen gene (OR = 1.9; 95% CI 1.1-3.4), diabetes (OR = 4.4; 95% CI 2.0-9.4) and hypertension (OR = 2.1; 95% CI 1.3-3.3) as risk factors predicting the coronary event. CONCLUSIONS: Our results provide no evidence of an association between ACE (I/D) or AT1 receptor polymorphism and coronary heart disease. However, homozygosity for the T allele of the angiotensinogen gene, diabetes and hypertension independently place individuals at higher risk of experiencing a coronary event on Grand Canary Island.
Subject(s)
Coronary Disease/genetics , Polymorphism, Genetic , Renin-Angiotensin System/genetics , Case-Control Studies , Female , Humans , Life Style , Male , Middle Aged , Multivariate Analysis , Risk FactorsABSTRACT
Introducción y objetivos. Estudios previos sobre la relación de la enfermedad coronaria y el polimorfismo de inserción/deleción de la enzima conversiva de la angiotensina (ECA [I/D]), el polimorfismo del gen del angiotensinógeno AGT M235T, o del receptor AT1 de la angiotensina II (A1166C) han demostrado resultados controvertidos. El objetivo de este estudio fue determinar la asociación entre estos polimorfismos génicos y el primer acontecimiento coronario en la población de Gran Canaria. Pacientes y método. Estudio de casos y controles ajustados según edad. Los casos (n = 304) se seleccionaron al padecer un primer acontecimiento coronario; los controles constituyen una muestra aleatoria poblacional (n = 315).Todos los sujetos fueron evaluados para los factores de riesgo clásicos. Se tomaron muestras sanguíneas para determinaciones analíticas y extracción de ADN. Las genotipificaciones se realizaron por PCR y análisis de restricción. Resultados. No se encontró asociación entre el polimorfismo ECA (I/D), AT1R (A1166C) y la enfermedad coronaria, mientras que la distribución de frecuencias de los genotipos del angiotensinógeno entre pacientes y controles (TT: 29 y 19 por ciento; MT: 48 y 50 por ciento; MM: 22 y 31 por ciento, respectivamente) resultaron estadísticamente diferentes (p = 0,003). El análisis multivariado identificó como factores predictores de acontecimiento coronario al genotipo TT del gen del angiotensinógeno (OR = 1,9; IC del 95 por ciento, 1,13,4), la diabetes (OR = 4,4; IC del 95 por ciento, 2,0-9,4) y la hipertensión (OR = 2,1; IC del 95 por ciento, 1,3-3,3).Conclusiones. No se ha observado asociación entre el polimorfismo ECA (I/D), AT1R (A1166C) y la enfermedad coronaria. Sin embargo, la homocigosis TT del gen del angiotensinógeno, la diabetes y la hipertensión arterial predisponen de manera independiente a la aparición de un primer acontecimiento coronario en la población canaria (AU)
