Effects of angiotensin II type 1 receptor blocker on bones in mice with type 1 diabetes induced by streptozotocin

Zhang, Yan; Diao, Teng Yue; Gu, Sa Sa; Wu, Shu; Gebru, Yoseph Asmelash; Chen, Xi; Wang, Jing Yu; Ran, Shu; Wong, Man Sau

doi:10.1177/1470320312471229

Cited by 19 publications

(14 citation statements)

References 31 publications

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“…Blockade of the RAS with ACEI and ARB inevitably disrupts the negative feedback loop that is critical for maintaining renin homeostasis, leading to compensatory induction of renin [5,41]. This is the main cause accounting for that the treatment with losartan (belongs to ARB) alone could not exert beneficial effects on diabetes-induced osteoporosis [42] and hyperglycemia-induced renal disease [5] in type 1 diabetic mice. The emerging clinical evidences Fig.…”

Section: Discussionmentioning

confidence: 96%

Renin inhibitor aliskiren exerts beneficial effect on trabecular bone by regulating skeletal renin-angiotensin system and kallikrein-kinin system in ovariectomized mice

et al. 2015

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Section: Discussionmentioning

confidence: 96%

Renin inhibitor aliskiren exerts beneficial effect on trabecular bone by regulating skeletal renin-angiotensin system and kallikrein-kinin system in ovariectomized mice

et al. 2015

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“…Agtr1a loss-of-function protects against bone loss in both age-related and ovariectomy (OVX)-induced osteoporosis mouse models [28]. Among all of the various in vivo studies on AngII signaling in bone, the protection against OVX-induced bone loss has been the most reproducible in mice [29] and has also been recapitulated in rat models [10,30]. Collective studies emphasize beneficial role to bone health by inactivating Agtr1 signaling.…”

Section: Discussionmentioning

confidence: 99%

Losartan increases bone mass and accelerates chondrocyte hypertrophy in developing skeleton

Chen

Grover

Sibai

et al. 2015

Molecular Genetics and Metabolism

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Angiotensin receptor blockers (ARBs) are a group of anti-hypertensive drugs that are widely used to treat pediatric hypertension. Recent application of ARBs to treat diseases such as Marfan syndrome or Alport syndrome has shown positive outcomes in animal and human studies, suggesting a broader therapeutic potential for this class of drugs. Multiple studies have reported a benefit of ARBs on adult bone homeostasis; however, its effect on the growing skeleton in children is unknown. We investigated the effect of Losartan, an ARB, in regulating bone mass and cartilage during development in mice. Wild type mice were treated with Losartan from birth until 6 weeks of age, after which bones were collected for microCT and histomorphometric analyses. Losartan increased trabecular bone volume vs. tissue volume (a 98% increase) and cortical thickness (a 9% increase) in 6-weeks old wild type mice. The bone changes were attributed to decreased osteoclastogenesis as demonstrated by reduced osteoclast number per bone surface in vivo and suppressed osteoclast differentiation in vitro. At the molecular level, Angiotensin II-induced ERK1/2 phosphorylation in RAW cells was attenuated by Losartan. Similarly, RANKL-induced ERK1/2 phosphorylation was suppressed by Losartan, suggesting a convergence of RANKL and angiotensin signaling at the level of ERK1/2 regulation. To assess the effect of Losartan on cartilage development, we examined the cartilage phenotype of wild type mice treated with Losartan in utero from conception to 1 day of age. Growth plates of these mice showed an elongated hypertrophic chondrocyte zone and increased Col10a1 expression level, with minimal changes in chondrocyte proliferation. Altogether, inhibition of the angiotensin pathway by Losartan increases bone mass and accelerates chondrocyte hypertrophy in growth plate during skeletal development.

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“…ANG II, active peptide within RAS, plays a pathological role in development of osteopenia and osteoporosis through activating osteoclastogenesis and inhibiting osteogenesis by binding to Type 1 receptor (AT1R; Nakai et al, ; Shimizu et al, ). In vivo and in vitro studies showed that the increased activity of skeletal RAS, especially the overactivation of the renin/renin receptor axis and the ACE/ANG II/AT1R signaling, was detrimental to bone tissue during hyperglycemia (Li et al, ; Yamamoto et al, ; Zhang et al, ; Zhang et al, ). Therefore, the RAS inhibitors, including renin inhibitor, ACE inhibitor (ACEI), and ANG II receptor blocker (ARB), exerted beneficial effects on skeletal system in animal studies (Zhang, Wang, Song, et al, ) and clinical studies (Yamamoto et al, ), even though these drugs in clinic are mainly prescribed for treating hypertension.…”

Section: Introductionmentioning

confidence: 99%

Tetrahydroxy stilbene glucoside protected against diabetes‐induced osteoporosis in mice with streptozotocin‐induced hyperglycemia

Zhang

Chen

et al. 2018

Phytotherapy Research

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Tetrahydroxy stilbene glucoside (TSG), an active component from medicinal herb Polygonum multiflorum Thunb, could block the activity of the tissue reninangiotensin system (RAS), which plays a critical role in development of diabetic osteoporosis. This study aimed to determine if TSG therapy could alleviate bone deteriorations in diabetic mouse model induced by streptozotocin. The diabetic mice showed the loss of trabecular bone mass and the changes of trabecular bone microarchitectural parameters as well as the increase in amount of tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts at the distal metaphysis of femur when compared with those of nondiabetic mice. Treatment with TSG significantly elevated calcium content in serum and bone and improved biological parameters of trabecular bone, accompanied by increasing messenger RNA (mRNA) expression of RUNX-2, COL-I, and OCN and protein expression of β-catenin as well as down-regulating protein expression of RAS components including renin and AT1R. In addition, TSG repressed diabetes-induced decrease in ratio of OPG/RANKL expression and increase in sclerostin expression in bone. The similar effects of TSG on osteoblasts-specific genes were found in MC3T3-E1 cells. Taken together, the present study demonstrated the osteopreserve effects of TSG in diabetic mice, and the underlying mechanism might be attributed to its regulation on osteogenesis and osteoclastogenesis.

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Effects of angiotensin II type 1 receptor blocker on bones in mice with type 1 diabetes induced by streptozotocin

Abstract: Local bone RAS functionally played a role in the development of type 1 diabetic osteoporosis, and losartan had no bone-sparing function in diabetes mice because of enhance skeletal RAS activity.

Cited by 19 publications

References 31 publications

Renin inhibitor aliskiren exerts beneficial effect on trabecular bone by regulating skeletal renin-angiotensin system and kallikrein-kinin system in ovariectomized mice

Renin inhibitor aliskiren exerts beneficial effect on trabecular bone by regulating skeletal renin-angiotensin system and kallikrein-kinin system in ovariectomized mice

Losartan increases bone mass and accelerates chondrocyte hypertrophy in developing skeleton

Tetrahydroxy stilbene glucoside protected against diabetes‐induced osteoporosis in mice with streptozotocin‐induced hyperglycemia

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