Angiotensin 1-7 alleviates aging-associated muscle weakness and bone loss, but is not associated with accelerated aging in ACE2-knockout mice

2019 ◽  
Vol 133 (18) ◽  
pp. 2005-2018 ◽  
Author(s):  
Satoko Nozato ◽  
Koichi Yamamoto ◽  
Hikari Takeshita ◽  
Yoichi Nozato ◽  
Yuki Imaizumi ◽  
...  
Keyword(s):  
Grip Strength ◽  
Muscle Weakness ◽  
Accelerated Aging ◽  
Renin Angiotensin System ◽  
Protective Role ◽  
Wild Type ◽  
Muscle Fibre Size ◽  
Physiological Aging ◽  
Grip Strength Measurement ◽  
The Impact

Abstract The angiotensin-converting enzyme 2 (ACE2)-angiotensin 1-7 (A1-7)-A1-7 receptor (Mas) axis plays a protective role in the renin–angiotensin system (RAS). We recently found that ACE2 knockout (ACE2KO) mice exhibit earlier aging-associated muscle weakness, and that A1-7 alleviates muscle weakness in aging mice. In the present study, we investigated the role of the A1-7-Mas pathway in the effect of ACE2 on physiological aging. Male wild-type, ACE2KO, and Mas knockout (MasKO) mice were subjected to periodical grip strength measurement, followed by administration of A1-7 or vehicle for 4 weeks at 24 months of age. ACE2KO mice exhibited decreased grip strength after 6 months of age, while grip strength of MasKO mice was similar to that of wild-type mice. A1-7 improved grip strength in ACE2KO and wild-type mice, but not in MasKO mice. Muscle fibre size was smaller in ACE2KO mice than that in wild-type and MasKO mice, and increased with A1-7 in ACE2KO and WT mice, but not in MasKO mice. Centrally nucleated fibres (CNFs) and expression of the senescence-associated gene p16INK4a in skeletal muscles were enhanced only in ACE2KO mice and were not altered by A1-7. ACE2KO mice, but not MasKO mice, exhibited thinning of peripheral fat along with increased adipose expression of p16INK4a. A1-7 significantly increased bone volume in wild-type and ACE2KO mice, but not in MasKO mice. Our findings suggest that the impact of ACE2 on physiological aging does not depend on the endogenous production of A1-7 by ACE2, while overactivation of the A1-7-Mas pathway could alleviate sarcopenia and osteoporosis in aged mice.

092 Effect of the dual orexin receptor antagonist (DORA) daridorexant on behaviour upon awakening in rats and dogs

SLEEP ◽  
2021 ◽  
Vol 44 (Supplement_2) ◽  
pp. A38-A39
Author(s):  
Giorgio Bergamini ◽  
Catherine Roch ◽  
Sean Durkin ◽  
Michel Steiner
Keyword(s):  
Grip Strength ◽  
Motor Skills ◽  
Muscle Weakness ◽  
Motor Behavior ◽  
Motor Impairment ◽  
Phase Behaviour ◽  
Fine Motor ◽  
Dependent Manner ◽  
The Impact ◽  
Time Point

Abstract Introduction The ability to be fast alert and to interact with the environment without motor impairment upon waking up, is a critical feature of natural sleep. DORAs represent a new class of insomnia medications that specifically inhibit the wake-promoting effects of orexin neuropeptides. Daridorexant is a potent and selective DORA under late stage development for the treatment of insomnia. Here, we assessed the impact of sleep-promoting doses of daridorexant on rats’ and dogs’ behaviour upon forced awakening. Zolpidem (a positive GABAA receptor modulator) was used as active comparator in rats because of its known negative impact on motor functions. Methods Rats were woken up at different time points after oral administration of daridorexant (10, 30, 100 mg/kg) or zolpidem (30, 100 mg/kg) during their inactive phase, and repeatedly subjected to two motor tasks: 1) the rotating rod test (lasting 120 sec, at each time point) assessing gross motor skills and coordination, and 2) the forepaw grip strength test assessing fine motor skills and muscle strength. Dogs were presented with food as an external, salient stimulus, three hours after administration of daridorexant in gelatin capsules (10, 30 or 90 mg/dog) during their active phase. Behaviour and signs of muscle weakness, after having woken up, were assessed by manual inspection of video recordings and concomitant electroencephalogram/electromyogram recordings. Results In both the rotarod and grip tests, daridorexant treatment had no effect on motor behavior at any dose or time point tested, while zolpidem significantly reduced the time spent on the rotarod and the grip strength in a dose and time-dependent manner (N=12/group; p<0.001;) (e.g. at 30 min post-dose, time spent on the rotarod was 84, 79–89 and 10–19 sec for vehicle, daridorexant and zolpidem, respectively). Dogs treated with daridorexant were able to wake up easily upon food presentation. They behaved and ate normally and did not show any signs of muscle weakness. Conclusion The type of sleep promoted by daridorexant is surmountable in rats and dogs and similar to physiological sleep. It allows animals to easily wake up, to behave normally without motor impairment and to respond efficiently to the environmental conditions. Support (if any) Funded by Idorsia Pharmaceuticals Ltd

FGF21 prevents low protein diet-induced renal inflammation in aged mice

2021 ◽  
Author(s):  
Han Fang ◽  
Sujoy Ghosh ◽  
Landon Sims ◽  
Kirsten P. Stone ◽  
Cristal M Hill ◽  
...  
Keyword(s):  
Transcriptional Activation ◽  
Renal Damage ◽  
Protective Role ◽  
Wild Type ◽  
Kidney Weight ◽  
Albumin Creatinine Ratio ◽  
Low Protein ◽  
The Impact ◽  
Protein Diets

Low protein diets extend lifespan through a comprehensive improvement in metabolic health across multiple tissues and organs. Many of these metabolic responses to protein restriction are secondary to transcriptional activation and release of FGF21 from the liver. However, the effects of a low protein (LP) diet on the kidney in the context of aging has not been examined. Therefore, the goal of the current study was to investigate the impact of chronic consumption of a LP diet on the kidney in aging mice lacking FGF21. Wild type (WT, C57BL/6J) and FGF21 KO mice were fed a normal protein (NP, 20% casein) or a LP (5% casein) diet ad libitum from 3 to19 months of age. The LP diet led to a decrease in kidney weight and urinary albumin/creatinine ratio in both WT and FGF21 KO mice. Although the LP diet produced only mild fibrosis and infiltration of leukocytes in WT kidneys, the effects were significantly exacerbated by the absence of FGF21. Accordingly, transcriptomic analysis showed that inflammation-related pathways were significantly enriched and upregulated in response to LP diet in FGF21 KO but not WT mice. Collectively, these data demonstrate that the LP diet negatively affected the kidney during aging, but in the absence of FGF21, the LP diet-induced renal damage and inflammation were significantly worse, indicating a protective role of FGF21 in the kidney.

scholarly journals Novel protective role for MAP kinase phosphatase 2 in inflammatory arthritis

RMD Open ◽  
2019 ◽  
Vol 5 (1) ◽  
pp. e000711
Author(s):  
Juliane Schroeder ◽  
Kirsty Ross ◽  
Kathryn McIntosh ◽  
Shilan Jabber ◽  
Stuart Woods ◽  
...  
Keyword(s):  
Inflammatory Arthritis ◽  
Neutrophil Migration ◽  
Protective Role ◽  
Leukotriene B4 ◽  
Mitogen Activated Protein Kinase ◽  
Wild Type ◽  
Map Kinase Phosphatase ◽  
Tnf Α ◽  
The Impact

ObjectivesWe have previously shown mitogen-activated protein kinase phosphatase 2 (MKP-2) to be a key regulator of proinflammatory cytokines in macrophages. In the study presented here, we investigated the role of MKP-2 in inflammatory arthritis with a particular focus on neutrophils.MethodsTo achieve this, we subjected MKP-2 deficient and wild type mice to collagen antibody induced arthritis, an innate model of arthritis, and determined disease pathology. To further our investigation, we depleted neutrophils in a prophylactic and therapeutic fashion. Last, we used chemotaxis assays to analyse the impact of MKP-2 deletion on neutrophil migration.ResultsMKP-2-/- mice showed a significant increase in disease pathology linked to elevated levels of proarthritic cytokines and chemokines TNF-α, IL-6 and MCP-1 in comparison to wild type controls. This phenotype is prevented or abolished after administration of neutrophil depleting antibody prior or after onset of disease, respectively. While MCP-1 levels were not affected, neutrophil depletion diminished TNF-α and reduced IL-6, thus linking these cytokines to neutrophils. In vivo imaging showed that MKP-2-/- mice had an increased influx of neutrophils into affected joints, which was higher and potentially prolonged than in wild type animals. Furthermore, using chemotaxis assays we revealed that MKP-2 deficient neutrophils migrate faster towards a Leukotriene B4 gradient. This process correlated with a reduced phosphorylation of ERK in MKP-2-/- neutrophils.ConclusionsThis is the first study to show a protective role for MKP-2 in inflammatory arthritis.

scholarly journals α2A-Adrenoceptors Modulate Renal Sympathetic Neurotransmission and Protect against Hypertensive Kidney Disease

2020 ◽  
Vol 31 (4) ◽  
pp. 783-798 ◽  
Author(s):  
Lydia Hering ◽  
Masudur Rahman ◽  
Henning Hoch ◽  
Lajos Markó ◽  
Guang Yang ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Knockout Mice ◽  
Renal Denervation ◽  
Renin Angiotensin System ◽  
Sympathetic Nerves ◽  
Protective Role ◽  
Renal Nerves ◽  
Wild Type ◽  
Renal Nerve

BackgroundIncreased nerve activity causes hypertension and kidney disease. Recent studies suggest that renal denervation reduces BP in patients with hypertension. Renal NE release is regulated by prejunctional α2A-adrenoceptors on sympathetic nerves, and α2A-adrenoceptors act as autoreceptors by binding endogenous NE to inhibit its own release. However, the role of α2A-adrenoceptors in the pathogenesis of hypertensive kidney disease is unknown.MethodsWe investigated effects of α2A-adrenoceptor–regulated renal NE release on the development of angiotensin II–dependent hypertension and kidney disease. In uninephrectomized wild-type and α2A-adrenoceptor–knockout mice, we induced hypertensive kidney disease by infusing AngII for 28 days.ResultsUrinary NE excretion and BP did not differ between normotensive α2A-adrenoceptor–knockout mice and wild-type mice at baseline. However, NE excretion increased during AngII treatment, with the knockout mice displaying NE levels that were significantly higher than those of wild-type mice. Accordingly, the α2A-adrenoceptor–knockout mice exhibited a systolic BP increase, which was about 40 mm Hg higher than that found in wild-type mice, and more extensive kidney damage. In isolated kidneys, AngII-enhanced renal nerve stimulation induced NE release and pressor responses to a greater extent in kidneys from α2A-adrenoceptor–knockout mice. Activation of specific sodium transporters accompanied the exaggerated hypertensive BP response in α2A-adrenoceptor–deficient kidneys. These effects depend on renal nerves, as demonstrated by reduced severity of AngII-mediated hypertension and improved kidney function observed in α2A-adrenoceptor–knockout mice after renal denervation.ConclusionsOur findings reveal a protective role of prejunctional inhibitory α2A-adrenoceptors in pathophysiologic conditions with an activated renin-angiotensin system, such as hypertensive kidney disease, and support the concept of sympatholytic therapy as a treatment.

scholarly journals Endogenous Long Pentraxin 3 Exerts a Protective Role in a Murine Model of Pulmonary Fibrosis

2021 ◽  
Vol 12 ◽  
Author(s):  
Federica Maccarinelli ◽  
Mattia Bugatti ◽  
Ander Churruca Schuind ◽  
Sara Ganzerla ◽  
William Vermi ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Murine Model ◽  
Lung Fibrosis ◽  
Protective Role ◽  
Pentraxin 3 ◽  
Wild Type ◽  
Fibroblast Activation ◽  
Fibrotic Process ◽  
Redundant Functions ◽  
The Impact

Pulmonary fibrosis is a progressive scarring disease of the lungs, characterized by inflammation, fibroblast activation, and deposition of extracellular matrix. The long pentraxin 3 (PTX3) is a member of the pentraxin family with non-redundant functions in innate immune responses, tissue repair, and haemostasis. The role played in the lungs by PTX3 during the fibrotic process has not been elucidated. In this study, the impact of PTX3 expression on lung fibrosis was assessed in an intratracheal bleomycin (BLM)-induced murine model of the disease applied to wild type animals, transgenic mice characterized by endothelial overexpression and stromal accumulation of PTX3 (Tie2-PTX3 mice), and genetically deficient Ptx3−/− animals. Our data demonstrate that PTX3 is produced during BLM-induced fibrosis in wild type mice, and that PTX3 accumulation in the stroma compartment of Tie2-PTX3 mice limits the formation of fibrotic tissue in the lungs, with reduced fibroblast activation and collagen deposition, and a decrease in the recruitment of the immune infiltrate. Conversely, Ptx3-null mice showed an exacerbated fibrotic response and decreased survival in response to BLM treatment. These results underline the protective role of endogenous PTX3 during lung fibrosis and pave the way for the study of novel PTX3-derived therapeutic approaches to the disease.

scholarly journals Double Deletion of Angiotensin II Type 2 and Mas Receptors Accelerates Aging‐Related Muscle Weakness in Male Mice

2021 ◽  
Author(s):  
Hikari Takeshita ◽  
Koichi Yamamoto ◽  
Masaki Mogi ◽  
Yu Wang ◽  
Yoichi Nozato ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Grip Strength ◽  
Muscle Weakness ◽  
Knockout Mice ◽  
Skeletal Muscles ◽  
Aging Process ◽  
Renin Angiotensin System ◽  
Male Mice ◽  
Double Deletion

Background The activation of AT2 (angiotensin II type 2 receptor ) and Mas receptor by angiotensin II and angiotensin‐(1‐7), respectively, is the primary process that counteracts activation of the canonical renin‐angiotensin system (RAS). Although inhibition of canonical RAS could delay the progression of physiological aging, we recently reported that deletion of Mas had no impact on the aging process in mice. Here, we used male mice with a deletion of only AT2 or a double deletion of AT2 and Mas to clarify whether these receptors contribute to the aging process in a complementary manner, primarily by focusing on aging‐related muscle weakness. Methods and Results Serial changes in grip strength of these mice up to 24 months of age showed that AT2/Mas knockout mice, but not AT2 knockout mice, had significantly weaker grip strength than wild‐type mice from the age of 18 months. AT2/Mas knockout mice exhibited larger sizes, but smaller numbers and increased frequency of central nucleation (a marker of aged muscle) of single skeletal muscle fibers than AT2 knockout mice. Canonical RAS‐associated genes, inflammation‐associated genes, and senescence‐associated genes were highly expressed in skeletal muscles of AT2/Mas knockout mice. Muscle angiotensin II content increased in AT2/Mas knockout mice. Conclusions Double deletion of AT2 and Mas in mice exaggerated aging‐associated muscle weakness, accompanied by signatures of activated RAS, inflammation, and aging in skeletal muscles. Because aging‐associated phenotypes were absent in single deletions of the receptors, AT2 and Mas could complement each other in preventing local activation of RAS during aging.

Subtle Impact of Akt1 and Akt3 on Exploratory Behavior in Gene Targeted Mice

2015 ◽  
Vol 223 (3) ◽  
pp. 173-180 ◽  
Author(s):  
Christina Leibrock ◽  
Michael Hierlmeier ◽  
Undine E. Lang ◽  
Florian Lang
Keyword(s):  
Forced Swimming Test ◽  
Open Field Test ◽  
Wild Type ◽  
Average Speed ◽  
Closed Area ◽  
Light Area ◽  
Swimming Test ◽  
The Impact ◽  
Center Area ◽  
Dark Transition

Abstract. The present study explored the impact of Akt1 and Akt3 on behavior. Akt1 (akt1-/-) and Akt3 (akt3-/-) knockout mice were compared to wild type (wt) mice. The akt1-/- mice, akt3-/- mice, and wt mice were similar in most parameters of the open-field test. However, the distance traveled in the center area was slightly but significantly less in akt3-/- mice than in wt mice. In the light/dark transition test akt1-/- mice had significantly lower values than wt mice and akt3-/- mice for distance traveled, number of rearings, rearing time in the light area, as well as time spent and distance traveled in the entrance area. They were significantly different from akt3-/- mice in the distance traveled, visits, number of rearings, rearing time in the light area, as well as time spent, distance traveled, number of rearings, and rearing time in the entrance area. In the O-maze the time spent, and the visits to open arms, as well as the number of protected and unprotected headdips were significantly less in akt1-/- mice than in wt mice, whereas the time spent in closed arms was significantly more in akt1-/- mice than in wt mice. Protected and unprotected headdips were significantly less in akt3-/- mice than in wt mice. In closed area, akt3-/- mice traveled a significantly larger distance at larger average speed than akt1-/- mice. No differences were observed between akt1-/- mice, akt3-/- mice and wt-type mice in the time of floating during the forced swimming test. In conclusion, akt1-/- mice and less so akt3-/ mice display subtle changes in behavior.

Aortic Stenosis, Aortic Regurgitation and Arterial Hypertension

2019 ◽  
Vol 17 (2) ◽  
pp. 180-190 ◽  
Author(s):  
V. Katsi ◽  
G. Georgiopoulos ◽  
D. Oikonomou ◽  
C. Aggeli ◽  
C. Grassos ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Aortic Stenosis ◽  
Aortic Regurgitation ◽  
Antihypertensive Agents ◽  
Renin Angiotensin System ◽  
Aortic Disease ◽  
Review Of The Literature ◽  
Angiotensin System ◽  
The Impact ◽  
Worse Prognosis

Background: Hypertension (HT) is an important risk factor for cardiovascular disease and might precipitate pathology of the aortic valve. </P><P> Objective: To investigate the association of HT with aortic dysfunction (including both aortic regurgitation and stenosis) and the impact of antihypertensive treatment on the natural course of underlying aortic disease. </P><P> Methods: We performed a systematic review of the literature for all relevant articles assessing the correlation between HT and phenotype of aortic disease. </P><P> Results: Co-existence of HT with aortic stenosis and aortic regurgitation is highly prevalent in hypertensive patients and predicts a worse prognosis. Certain antihypertensive agents may improve haemodynamic parameters (aortic jet velocity, aortic regurgitation volume) and remodeling of the left ventricle, but there is no strong evidence of benefit regarding clinical outcomes. Renin-angiotensin system inhibitors, among other vasodilators, are well-tolerated in aortic stenosis. </P><P> Conclusion: Several lines of evidence support a detrimental association between HT and aortic valve disease. Therefore, HT should be promptly treated in aortic valvulopathy. Despite conventional wisdom, specific vasodilators can be used with caution in aortic stenosis.

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