Renin Inhibition Improves Ovariectomy-Induced Osteoporosis of Lumbar Vertebra in Mice

Abstract

The skeletal renin-angiotensin system (RAS) is involved in the progression of osteoporosis and the active peptide within the RAS, angiotensin II (ANG II), has deleterious effects on bones. This study was performed to investigate whether suppression of the rate-limiting step of the RAS cascade by the renin inhibitor aliskiren has a benefit on trabecular bone in osteoporotic mice. A postmenopausal osteoporosis model was induced by bilateral ovariectomy. The ovariectomized (OVX) mice were treated with a low (5 mg/kg) or high (25 mg/kg) dose of aliskiren for 6 weeks. Micro-computed tomography was performed to detect trabecular bone parameters of lumbar vertebra and to obtain 3-dimensional (3D) images. Treatment with aliskiren markedly increased bone volume over total volume (p<0.05), trabecular bone number (p<0.05), connectivity density (p<0.05), and bone mineral density (p<0.05) and reduced trabecular bone separation (p<0.05) compared to vehicle-treated OVX mice. Similarly, the 3D images were consistent with the quantitative data that showed aliskiren could markedly reverse the ovariectomy-induced pathological changes of trabecular bone. Thus, this study indicated that the treatment of estrogen-deficient mice with aliskiren could markedly increase bone mass and improve trabecular bone structure, suggesting its potential application in treating postmenopausal osteoporosis.Key words renin-angiotensin system; aliskiren; bone; osteoporosis; ovariectomy 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) Within classical RAS, liver secreted angiotensinogen (AGT) is enzymatically cleaved to angiotensin (ANG) I by kidney-derived renin. ANG I is, hereafter, cleaved by angiotensin-converting enzyme (ACE) to the effector hormone ANG II. It is now evident that the components of RAS, in addition to the classical pathway, are expressed and act locally in multiple tissues, 2) such as insulin secretion, 3) glomerular sclerosis, 4) renal inflammation, 5) atherosclerosis, 6) cardiac hypertrophy 7) and brain disorders. 8)Recent studies showed that the components of RAS, such as renin, ACE, and ANG II receptors, are also expressed in the local milieu of bone. 9,10) Functional studies revealed that ANG II could stimulate the differentiation and activity of osteoclasts in vivo 11) and in vitro, 12) and aggravate the loss of bone minerals in rats with osteoporosis induced by estrogen deficiency, 11) furthermore, the ANG II type 1 receptor knockout mice showed high bone mass.13) In addition, we recently demonstrated that the local RAS in bone was involved in age-related osteoporosis of aging mice, 14) bone deteriorations of mice with either obstructive nephropathy 15) or type 1 diabetes, 16) and others elucidated the involvement of skeletal RAS in the process of fracture healing in a mouse femur fracture model. 17) Therefore, the local RAS displays important biological actions in bone tissue.Currently, besides the applications in the...

Gastroprotective effects of arctigenin of Arctium lappa L. on a rat model of gastric ulcers

“…This chronic ulcer model, which highly resembles human chronic ulcers in terms of pathological features and healing mechanisms, is utilized to develop novel anti-ulcer medication, which may potentially prevent ulcer relapse or enhance ulcer healing (26). Acetic acid is reported to produce ulcers by gastric obstruction leading to increased quantities of acidic gastric juice (27,28). In the current study, arctigenin caused significant reductions in gastric lesions at all doses tested, when compared with the vehicle group (Fig.…”

Inhibition of tanshinone IIA on renin activity protected against osteoporosis in diabetic mice

“…The first among these treatments was the angiotensin-converting enzyme inhibitors (ACEIs), followed by the ANG II receptor blockers (ARBs), while the major problem associated with the application of these drugs is the compensatory rise of renin due to the disruption of the feedback inhibition of renin production (Zhang et al 2008). Additionally, given the contradictory results about the effects of RAS inhibitors including ACEIs and ARBs on skeletal system in previous animal and clinical studies (Kwok et al 2012;Zhang YF et al 2012;Yang et al 2016), and renin inhibitor aliskiren consistently exerted protection from bone loss of osteoporotic animals (Zhang FY et al 2014;Zhang Y et al 2016aZhang Y et al , 2016b, it might be a challenge in exploring bioactive ingredient targeting renin activity. Since renin is the rate-limiting enzyme of the RAS (Zhang Y et al 2016a(Zhang Y et al , 2016b, tremendous research efforts have been performed to identify active renin inhibitors and some drug candidates have entered into clinical trials (Sun et al 2015).…”

“…In vivo and in vitro studies showed that the increased activity of skeletal RAS, especially the over-activation of the renin/ANG II/AT1R signalling at high glucose state, was detrimental to bone tissue (Zhang Y et al , 2016a(Zhang Y et al , 2016bLi et al 2015;Yamamoto et al 2015). Since renin is the rate-limiting enzyme of the RAS cascade (Zhang Y et al 2012), the renin inhibitor like aliskiren exerted beneficial effects on skeletal system in animal studies (Zhang FY et al 2014;Zhang Y et al 2016aZhang Y et al , 2016b. While the therapeutic reagents derived from natural products and traditional herbs acting on the renin/ANG II/AT1R pathway are very limited.…”

Effects of 1,25-dihydroxyvitamin D3 on the local bone renin-angiotensin system in a murine model of glucocorticoid-induced osteoporosis

“…A study by Zhang et al (39) reported that vitamin D was able to inhibit RAS activity in the kidney, improve renal function and prevent the occurrence of nephritis and fibrosis in mice caused by long-term hyperglycemia or unilateral ureteral obstruction. In the present study, 1,25(OH) 2 D 3 treatment improved the quality of cancellous bone in GIOP mice by inhibiting local RAS activity in bone tissue through a reduction in the generation of Ang II, thus downregulating the expression of osteoclast factors that may reduce bone resorption activity.…”