RESUMEN
In the present study, we tested the hypothesis that there are significant sex differences in angiotensin II (Ang II)-induced hypertension and kidney injury using male and female wildtype (WT) and proximal tubule-specific AT1a receptor knockout mice (PT-Agtr1a-/-). Twelve groups (n=8-12 per group) of adult male and female WT and PT-Agtr1a-/- mice were infused with a pressor dose of Ang II via osmotic minipump for 2 weeks (1.5 mg/kg/day, i.p.) and simultaneously treated with or without losartan (20 mg/kg/day, p.o.) to determine the respective roles of AT1a receptors in the proximal tubules versus systemic tissues. Basal systolic, diastolic, and mean arterial pressure were approximately 13 ± 3 mmHg lower (P<0.01), while basal 24-h urinary Na+, K+, and Cl- excretion were significantly higher in both male and female PT-Agtr1a-/- mice than WT controls (P<0.01) without significant sex differences between different strains. Both male and female WT and PT-Agtr1a-/- mice developed hypertension (P<0.01), and the magnitudes of the pressor responses to Ang II were similar between male and female WT and PT-Agtr1a-/- mice (n.s.). Likewise, Ang II-induced hypertension was significantly attenuated in both male and female PT-Agtr1a-/- mice (P<0.01). Furthermore, losartan attenuated the hypertensive responses to Ang II to similar extents in both male and female WT and PT-Agtr1a-/- mice. Finally, Ang II-induced kidney injury was attenuated in PT-Agtr1a-/- mice (P<0.01). In conclusion, the present study demonstrates that deletion of AT1a receptors in the proximal tubules of the kidney attenuates Ang II-induced hypertension and kidney injury without revealing significant sex differences.
Asunto(s)
Presión Arterial , Hipertensión/metabolismo , Enfermedades Renales/metabolismo , Túbulos Renales Proximales/metabolismo , Receptor de Angiotensina Tipo 1/metabolismo , Sistema Renina-Angiotensina , Angiotensina II , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Animales , Antihipertensivos/farmacología , Presión Arterial/efectos de los fármacos , Modelos Animales de Enfermedad , Femenino , Fibrosis , Hipertensión/inducido químicamente , Hipertensión/fisiopatología , Hipertensión/prevención & control , Enfermedades Renales/inducido químicamente , Enfermedades Renales/fisiopatología , Enfermedades Renales/prevención & control , Túbulos Renales Proximales/efectos de los fármacos , Túbulos Renales Proximales/fisiopatología , Túbulos Renales Proximales/ultraestructura , Losartán/farmacología , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Receptor de Angiotensina Tipo 1/genética , Sistema Renina-Angiotensina/efectos de los fármacos , Caracteres Sexuales , Factores Sexuales , Transducción de SeñalRESUMEN
Hypertension is well recognized to be the most important risk factor for cardiovascular diseases, stroke, and end-stage kidney failure. A quarter of the world's adult populations and 46% of the US adults develop hypertension and currently require antihypertensive treatments. Only 50% of hypertensive patients are responsive to current antihypertensive drugs, whereas remaining patients may continue to develop cardiovascular, stroke, and kidney diseases. The mechanisms underlying the poorly controlled hypertension remain incompletely understood. Recently, we have focused our efforts to uncover additional renal mechanisms, pathways, and therapeutic targets of poorly controlled hypertension and target organ injury using novel animal models or innovative experimental approaches. Specifically, we studied and elucidated the important roles of intratubular, intracellular, and mitochondrial angiotensin II (Ang II) system in the development of Ang II-dependent hypertension. The objectives of this invited article are to review and discuss our recent findings that (a) circulating and intratubular Ang II is taken up by the proximal tubules via the (AT1) AT1a receptor-dependent mechanism, (b) intracellular administration of Ang II in proximal tubule cells or adenovirus-mediated overexpression of an intracellular Ang II fusion protein selectively in the mitochonria of the proximal tubules induces blood pressure responses, and (c) genetic deletion of AT1 (AT1a) receptors or the Na+/H+ exchanger 3 selectively in the proximal tubules decreases basal blood pressure and attenuates Ang II-induced hypertension. These studies provide a new perspective into the important roles of the intratubular, intracellular, and mitochondrial angiotensin II/AT1 (AT1a) receptor signaling in Ang II-dependent hypertensive kidney diseases.
RESUMEN
[Figure: see text].
Asunto(s)
Angiotensina II/metabolismo , Presión Sanguínea/fisiología , Hipertensión/metabolismo , Túbulos Renales Proximales/metabolismo , Receptor de Angiotensina Tipo 1 , Intercambiador 3 de Sodio-Hidrógeno/metabolismo , Animales , Modelos Animales de Enfermedad , Técnicas de Inactivación de Genes/métodos , Tasa de Filtración Glomerular , Ratones , Natriuresis/fisiología , Receptor de Angiotensina Tipo 1/genética , Receptor de Angiotensina Tipo 1/metabolismo , Transducción de SeñalRESUMEN
Children with obesity have a high risk of developing cardiovascular disease and hypertension, which is associated with the renin-angiotensin system (RAS) activation and kallikrein-kinin system (KKS) inactivation. Although recent studies have identified several peptide-based biomarkers for obesity, circulating peptides from the RAS and KKS in adolescents with obesity have not been described. The aim of this study was to examine circulating levels of RAS and KKS peptides in adolescents with obesity to investigate the turnover of these peptides and their relationship to metabolic disorders resulting from weight gain. The subjects (n = 104) were divided into normal weight (NW), overweight (OW), obese (OB), and morbidly obese (MO) groups. Anthropometric profiles were created by measuring height, weight, blood pressure, and skinfolds. Plasma levels of Ang I, II, (1-7), BK, and des-Arg9BK were quantified by high-performance liquid chromatography. The levels were as follows: Ang-(1-7)-MO 58.3 ± 50, OB 223.2 ± 150, OW 318.6 ± 190, NW 479.1 ± 160 pmol/mL, and Bradykinin (BK)-MO 367.6 ± 103, OB 253.8 ± 130, OW 484 ± 279, NW 874.9 ± 385 pmol/mL. Ang-(1-7) correlated inversely with weight, body mass index, leptin, diastolic blood pressure, and systolic blood pressure. BK and Ang-(1-7) levels correlated inversely with skinfolds, waist-hip ratio (WHR), leptin, and arm circumference. BK levels correlated with adiponectin and Ang-(1-7) levels. Plasma Ang I levels were higher in the MO and OB groups than in the NW group, but plasma Ang II levels were similar in all groups. We suggest that Ang-(1-7) and des-Arg9BK metabolites are novel biomarkers of childhood obesity that are important for determining treatment strategies.