RESUMEN
Some combinations of antihypertensive agents were shown to reduce proteinuria in patients with renal failure. However, preventive effects of such combinations on renal structure and function are presently unknown when treatment is administered before the onset of renal abnormalities. We thus investigated the long-term effects of an angiotensin-converting enzyme (ACE) inhibitor (perindopril)/diuretic (indapamide) combination (per/ind) in the Zucker rat, a classical model of chronic renal failure associated with obesity, hyperlipidemia, and insulin resistance. Two-month-old lean and obese Zucker rats, presenting normal renal structure and function at this young age, received per/ind (0.76 + 0.24 mg/kg of body weight/day) or the vehicle of this combination by daily gavage. After 8.5 consecutive months of treatment, those 10.5-month-old rats were used for determination of renal structural and functional parameters which were examined using standard renal clearance experiments and kidney tissue analysis. Per/ind prevented focal and segmental glomerular hyalinosis and tubulo-interstitial damage in obese rats. Treatment was also associated with a significant reduction in several staining markers of glomerular and interstitial fibrosis. The hypertrophy of superficial glomeruli and the mesangial expansion of deep glomeruli observed in control rats were reduced in per/ind-treated obese rats. The severe proteinuria observed in 10.5-month-old control obese rats was prevented by per/ind, while glomerular filtration and renal hemodynamic parameters reached similar values to those obtained in lean animals. These results show that long-term treatment with this ACE inhibitor/diuretic combination protects renal structure and function in the obese Zucker rat, emphasizing the potential efficiency of such therapy in renal failure prevention.
Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Diuréticos/uso terapéutico , Indapamida/uso terapéutico , Perindopril/uso terapéutico , Proteinuria/prevención & control , Insuficiencia Renal/prevención & control , Inhibidores de la Enzima Convertidora de Angiotensina/administración & dosificación , Inhibidores de la Enzima Convertidora de Angiotensina/farmacocinética , Animales , Diuréticos/administración & dosificación , Diuréticos/farmacocinética , Combinación de Medicamentos , Fibrosis/prevención & control , Indapamida/administración & dosificación , Indapamida/farmacocinética , Pruebas de Función Renal , Masculino , Tasa de Depuración Metabólica , Obesidad/complicaciones , Perindopril/administración & dosificación , Perindopril/farmacocinética , Proteinuria/etiología , Ratas , Ratas Zucker , Insuficiencia Renal/etiología , Insuficiencia Renal/patologíaRESUMEN
Chronic renal failure often induces left ventricular hypertrophy. We assessed whether the heart is affected in the Zucker obese rat, a model of chronic renal failure associated with obesity, glucose intolerance, and insulin resistance without hypertension or hyperglycemia. After systemic blood pressure measurement, the heart, the aorta, and the kidneys were removed from anesthetized 9- and 13-mo-old Zucker obese and lean control male rats (n = 33, n = 24, n = 25, and n = 21, respectively). Determination of left ventricular geometry, quantification of myocardium collagen density, and measurement of heart antioxidant enzyme activity were made, as well as aorta and kidney parameters. Mean blood pressure remained at a normal range whatever the age and group considered. Whereas kidney structure and function were severely impaired, no sign of myocardial infarction or inflammatory process was noticed. A moderate left ventricular hypertrophy was observed in 13-mo-old obese rats. While heart malondialdehyde was stable with age and among groups, antioxidant enzyme activity was higher in obese rats. In conclusion, in the absence of hypertensive or hyperglycemic disorders, the heat seems to display a sufficient line of defense against oxidative stress during the development of cardiac hypertrophy.