Kinin B1 Receptor Promotes Neurogenic Hypertension Through Activation of Centrally Mediated Mechanisms

Sriramula, Srinivas; Lazartigues, Eric

doi:10.1161/hypertensionaha.117.09744

Cited by 15 publications

(40 citation statements)

References 44 publications

(58 reference statements)

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“…Evidence for a possible crosstalk between glutamate-induced excitotoxicity and impairment of ACE2 activity in primary cortical neurons has been reported in our previous study [ 8 ]. On the other hand, B1R blockade can reduce neuroinflammation, prevent autonomic dysfunction and sympathoexcitation, and attenuate hypertension in a mouse model of neurogenic hypertension [ 20 ]. However, the crosstalk between glutamate and B1R has not been established.…”

Section: Discussionmentioning

confidence: 99%

“…Western blots were performed on primary hypothalamic neuronal homogenates, as described previously [ 20 , 40 ]. Neuron samples were homogenized in 1X lysis buffer containing protease and phosphatase inhibitors cocktail (Roche) and incubated on ice for 15 min.…”

Section: Methodsmentioning

confidence: 99%

“…Activation of B1R-mediated signaling pathways is implicated in the pathogenesis of various cardiovascular diseases that are associated with or induced by inflammation [ 16 ]. We previously showed that activation of B1R in the brain hypothalamic paraventricular nucleus resulted in elevated neuroinflammation, oxidative stress and sympathoexcitation, leading to the development of neurogenic hypertension [ 20 ]. We also demonstrated evidence for ADAM17-mediated ACE2 shedding in the neurons [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

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Activation of Kinin B1R Upregulates ADAM17 and Results in ACE2 Shedding in Neurons

Parekh

Sriramula

2020

IJMS

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Angiotensin converting enzyme 2 (ACE2) is a critical component of the compensatory axis of the renin angiotensin system. Alterations in ACE2 gene and protein expression, and activity mediated by A Disintegrin And Metalloprotease 17 (ADAM17), a member of the “A Disintegrin And Metalloprotease” (ADAM) family are implicated in several cardiovascular and neurodegenerative diseases. We previously reported that activation of kinin B1 receptor (B1R) in the brain increases neuroinflammation, oxidative stress and sympathoexcitation, leading to the development of neurogenic hypertension. We also showed evidence for ADAM17-mediated ACE2 shedding in neurons. However, whether kinin B1 receptor (B1R) activation has any role in altering ADAM17 activity and its effect on ACE2 shedding in neurons is not known. In this study, we tested the hypothesis that activation of B1R upregulates ADAM17 and results in ACE2 shedding in neurons. To test this hypothesis, we stimulated wild-type and B1R gene-deleted mouse neonatal primary hypothalamic neuronal cultures with a B1R-specific agonist and measured the activities of ADAM17 and ACE2 in neurons. B1R stimulation significantly increased ADAM17 activity and decreased ACE2 activity in wild-type neurons, while pretreatment with a B1R-specific antagonist, R715, reversed these changes. Stimulation with specific B1R agonist Lys-Des-Arg9-Bradykinin (LDABK) did not show any effect on ADAM17 or ACE2 activities in neurons with B1R gene deletion. These data suggest that B1R activation results in ADAM17-mediated ACE2 shedding in primary hypothalamic neurons. In addition, stimulation with high concentration of glutamate significantly increased B1R gene and protein expression, along with increased ADAM17 and decreased ACE2 activities in wild-type neurons. Pretreatment with B1R-specific antagonist R715 reversed these glutamate-induced effects suggesting that indeed B1R is involved in glutamate-mediated upregulation of ADAM17 activity and ACE2 shedding.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Activation of Kinin B1R Upregulates ADAM17 and Results in ACE2 Shedding in Neurons

Parekh

Sriramula

2020

IJMS

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“…Studies pharmacologically targeting the two receptors also revealed differential effects with B1R expression strongly responsive to inflammation (Sriramula and Lazartigues, 2017) and to changes in the environment (Ongali et al, 2003, Arganaraz et al, 2004. Furthermore, blockade of B1R in rats led to the improvement of cognitive function and agerelated cognitive decline (Prediger et al, 2008, Bitencourt et al, 2017.…”

Section: Discussionmentioning

confidence: 99%

Bradykinin B2 receptor is essential to running-induced cell proliferation in the adult mouse hippocampus

et al. 2018

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Physical exercise is a strong external effector that induces precursor cell proliferation in the adult mouse hippocampus. Research into mechanisms has focused on central changes within the hippocampus and we have established that serotonin is the signaling factor that transduces physical activity into adult neurogenesis. Less focus has been given on potential peripheral signals that may cause pro-mitotic running effects. Vasoactive kinin peptides are important for blood pressure regulation and inflammatory processes to maintain cardiovascular homeostasis. Acting via the two receptors termed B1 (B1R) and B2R, the peptides also function in the brain. In particular, studies attribute B2R a role in cell proliferation and differentiation into neurons in vitro. Here, we determined B1R and B2R mRNA expression levels in the adult mouse hippocampus and prefrontal cortex in vivo, and in response to running exercise. Using mice depleted in either or both receptors, B1-knockout (KO), B2KO and B1/2KO we observed changes in running performance overnight and in running distances. However, voluntary exercise led to the known pro-mitotic effect in the dentate gyrus of B1KO mice while it was attenuated in B2KO accompanied by an increase in microglia cells. Our data identify B2R as an important factor in running-induced precursor cell proliferation.

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“…C57Bl6/J male mice (10–12 weeks old, n = 3/group) were anesthetized with isoflurane (2%) and implanted subcutaneously with a DOCA (1 mg/g body weight) pellet and switched to a 1% NaCl drinking solution, as described previously (Sriramula and Lazartigues 2017 ). After 3 weeks, mice were euthanized and the hypothalamus was dissected for protein extraction and Western blotting analysis, as mentioned above.…”

Section: Methodsmentioning

confidence: 99%

The Actin Bundling Protein Fascin-1 as an ACE2-Accessory Protein

et al. 2020

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We have previously shown that angiotensin-converting enzyme 2 (ACE2), an enzyme counterbalancing the deleterious effects of angiotensin type 1 receptor activation by production of vasodilatory peptides Angiotensin (Ang)-(1-9) and Ang-(1-7), is internalized and degraded in lysosomes following chronic Ang-II treatment. However, the molecular mechanisms involved in this effect remain unknown. In an attempt to identify the accessory proteins involved in this effect, we conducted a proteomic analysis in ACE2-transfected HEK293T cells. A single protein, fascin-1, was found to differentially interact with ACE2 after Ang-II treatment for 4 h. The interactions between fascin-1 and ACE2 were confirmed by confocal microscopy and co-immunoprecipitation. Overexpression of fascin-1 attenuates the effects of Ang-II on ACE2 activity. In contrast, downregulation of fascin-1 severely decreased ACE2 enzymatic activity. Interestingly, in brain homogenates from hypertensive mice, we observed a significant reduction of fascin-1, suggesting that the levels of this protein may change in cardiovascular diseases. In conclusion, we identified fascin-1 as an ACE2-accessory protein, interacting with the enzyme in an Ang-II dependent manner and contributing to the regulation of enzyme activity.

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Kinin B1 Receptor Promotes Neurogenic Hypertension Through Activation of Centrally Mediated Mechanisms

Cited by 15 publications

References 44 publications

Activation of Kinin B1R Upregulates ADAM17 and Results in ACE2 Shedding in Neurons

Activation of Kinin B1R Upregulates ADAM17 and Results in ACE2 Shedding in Neurons

Bradykinin B2 receptor is essential to running-induced cell proliferation in the adult mouse hippocampus

The Actin Bundling Protein Fascin-1 as an ACE2-Accessory Protein

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