Thesis (Ph.D.) - Cairo University - Faculty of Pharmacy - Department of Pharmacology and Toxicology

Background: Osteoporosis is a worldwide epidemiological problem characterized by impaired bone mass and micro-architecture. Recently, the correlation between renin angiotensin system (RAS) and bone structure and metabolism was established. Angiotensin (Ang) II was found to induce bone loss and resorption through its angiotensin type 1 receptor (AT1R). Moreover, RAS inhibitory medications including angiotensin receptors blockers (ARB) and angiotensin converting enzyme inhibitors (ACEI) were found to attenuate this effect. The RAS is more complex than it was initially anticipated and due to several novel components being discovered recently. Ang1-7 is a heptapeptide, endogenous molecule of the RAS, which binds to its G-protein-coupled receptor, Mas receptor, and is considered the beneficial peptide of the RAS. Biological effects of Ang1-7/Mas receptor axis are often opposite to those of the AngII/AT1R axis. Objectives: Accordingly, this study was designed to study the effect of Ang1-7 on healthy and osteoporotic bone. Furthermore, the present study investigated whether the osteoprotective effects of ARB and ACEI are mediatedvia the Ang1-7/Mas receptor axis. Methods: Ovariectomized (OVX) Wistar albino rats were used in the present study as a model for osteoporosis. After 8 weeks of a bilateral ovariectomy and sham operations, animals were divided into 16 groups. With exception of the control groups, OVX and sham animals received (1) Ang1-7, (2) Mas receptor blocker (A-779), (3) Ang1-7+A-779, (4) ARB (losartan), (5) losartan + A-779, (6) ACEI (captopril) and (7) captopril + A-799 for the following six weeks. At the end of treatment period, urine samples were taken then animals were sacrificed to collect serum and femoral bone samples. Bone turnover biomarkers were measured in urine and serum samples using ELISA technique. In addition, femoral bones were used to estimate morphometric parameters by micro-computed tomography (micro-CT). Minerals levels were also determined in digested bone, serum, and urine samples by inductive coupled plasma mass spectroscopy (ICP-MS). Finally, the expressions of different RAS molecules, enzymes and receptors as well as osteoclastogenesis modulating factors were determined in the femur heads using western blot techniques.

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