Involvement of Renin–Angiotensin System in Damage of Angiotensin-Converting Enzyme Inhibitor Captopril on Bone of Normal Mice

Abstract

This study was performed to investigate the effect of angiotensin-converting enzyme inhibitor, captopril, on bone metabolism and histology, and the action of captopril on the components of the skeletal reninangiotensin system (RAS) and bradykinin receptor in normal male mice. The mice were orally administered captopril (10 mg/kg) for 4 weeks with vehicle-treated mice as normal control. The histology of trabecular bone at the distal femoral end was determined by hematoxylin & eosin, Safranin O and Masson-Trichrome staining. The captopril-treated mice showed a decreased level of testosterone ( p<0.05) and procollagen type I N-terminal propeptide (p<0.05) in serum as compared to those in the control group. Captopril has detrimental effects on trabecular bone as demonstrated by the loss of cancellous bone mass and network connections as well as changes to the chondrocytes zone. The expression of angiotensin-converting enzyme (p<0.05), renin receptor (p<0.01), angiotensin II (p<0.05) and bradykinin receptor 2 (p<0.05) was significantly up-regulated following the captopril treatment. Thus, the potential underlying mechanism of the damage of captopril on bone can be attributed the increased activity of local bone RAS and the activation of bradykinin receptor.Key words renin-angiotensin system; bradykinin receptor; captopril; bone The renin-angiotensin system (RAS) is a hormonal cascade that is thought to act as a master controller of blood pressure and fluid balance within the body.1) In addition to the systemic RAS, there is a fully functional RAS in local tissue, which is postulated to participate in various physiological and pathological processes such as insulin secretion, 2) glomerular sclerosis, 3) renal inflammation, 4) atherosclerosis, 5) and cardiac hypertrophy. 6) Recent in vivo studies showed that the components of RAS, such as renin, angiotensin-converting enzyme (ACE), and angiotensin II (Ang II) receptors, were expressed in the local milieu of bone, [7][8][9][10] and in vitro study identified the expression of Ang II receptors in primary osteoblasts derived from newborn mouse calvaria, 7) indicating the components of RAS are expressed locally in bone microenvironment. Our further animal studies demonstrated that the local RAS in bone was involved in age-related osteoporosis of aging mice, 11) and bone deteriorations of mice with either obstructive nephropathy 12) or type 1 diabetes.13) Other groups elucidated the involvement of skeletal RAS in the process of fracture healing in a mouse femur fracture model, 14) and the steroid-induced osteonecrosis in rabbits 10) as well as the development of postmenopausal osteoporosis in ovariectomized (OVX) animal models 15,16) and glucocorticoid-induced osteoporosis. 9) Therefore, it concludes that the local RAS exists in bone tissue and plays an important role in local bone metabolism.The main effector peptide Ang II in RAS is formed from angiotensin I by the action of ACE, a key molecule in this system. Patients treated with an ACE inhibitor (ACEI) showed an increas...

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