Kinin B1 Receptor Blockade Prevents Angiotensin II-induced Neuroinflammation and Oxidative Stress in Primary Hypothalamic Neurons

Parekh, Rohan Umesh; Robidoux, Jacques; Sriramula, Srinivas

doi:10.1007/s10571-019-00778-1

Cited by 25 publications

(33 citation statements)

References 53 publications

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“…We have previously demonstrated that ACE2 levels within tissues and cells can be modified by post translational mechanisms such as AT1R-dependent internalization processes [9] and AT1R-independent glutamate-induced ACE2 ectodomain shedding via ADAM17 [8]. Recently, we showed direct evidence for involvement of B1R in neuroinflammation and oxidative stress in neurons induced by Ang II stimulation and AT1R activation [32]. However, no prior studies have investigated the role of B1R in altering ADAM17 activity and its effect on ACE2 shedding in neurons.…”

Section: Discussionmentioning

confidence: 98%

“…Wildtype (WT) C57Bl/6NJ mice were purchased from the Jackson Laboratory. Primary hypothalamic neurons were cultured and maintained according to previously published methods [8,32]. Briefly, neonatal or 1-day-old mouse pups were anesthetized with isoflurane (4%) in an oxygen flow (1 L/min) before decapitation and brains were collected in ice-cold Hank's balanced salt solution (HBSS) (14175-079 Gibco, New York, NY, USA).…”

Section: Primary Neuronal Cell Culturementioning

confidence: 99%

“…Hypothalamic primary neurons were cultured for at least 10 days and then used for further experiments. The treatment durations and doses of LDABK (300 nM), R715 (10 μM), HOE-140 (10 μM), and glutamate (10 μM) are based on our preliminary studies and published literature [8,32]. Figure 6.…”

Section: Primary Neuronal Cell Culturementioning

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: 98%

Section: Primary Neuronal Cell Culturementioning

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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“…On the other hand, it is possible that the reduction in B1R expression could be secondary to lower inflammation caused by enalapril effects on other biological targets, such as the decrease of AngII production. Moreover, it has been shown that AT1R activation by AngII directly increases B1R expression (Parekh et al, 2019). AngII is capable of inducing kinin B1R via AT1R by releasing endothelin-1 and activating the endothelin receptor A (Morand-Contant et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Angiotensin-Converting Enzyme Inhibitor Protects Against Cisplatin Nephrotoxicity by Modulating Kinin B1 Receptor Expression and Aminopeptidase P Activity in Mice

Estrela

Wasinski

Gregnani

et al. 2020

Front. Mol. Biosci.

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Cisplatin is a highly effective chemotherapeutic agent. However, its use is limited by nephrotoxicity. Enalapril is an angiotensin I-converting enzyme inhibitor used for the treatment of hypertension, mainly through the reduction of angiotensin II formation, but also through the increase of kinins half-life. Kinin B1 receptor is associated with inflammation and migration of immune cells into the injured tissue. We have previously shown that the deletion or blockage of kinin B1 and B2 receptors can attenuate cisplatin nephrotoxicity. In this study, we tested enalapril treatment as a tool to prevent cisplatin nephrotoxicity. Male C57Bl/6 mice were divided into 3 groups: control group; cisplatin (20 mg/kg i.p) group; and enalapril (1.5 mg;kg i.p) + cisplatin group. The animals were treated with a single dose of cisplatin and euthanized after 96 h. Enalapril was able to attenuate cisplatin-induced increase in creatinine and urea, and to reduce tubular injury and upregulation of apoptosis-related genes, as well as inflammatory cytokines in circulation and kidney. The upregulation of B1 receptor was blocked in enalapril + cisplatin group. Carboxypeptidase M expression, which generates B1 receptor agonists, is blunted by cisplatin + enalapril treatment. The activity of aminopeptidase P, a secondary key enzyme able to degrade kinins, is restored by enalapril treatment. These findings were confirmed in mouse renal epithelial tubular cells, in which enalaprilat (5 µM) was capable of decreasing tubular injury and inflammatory markers. We treated mouse renal epithelial tubular cells with cisplatin (100 µM), cisplatin+enalaprilat and cisplatin+enalaprilat+apstatin (10 µM). The results showed that cisplatin alone decreases cell viability, cisplatin plus enalaprilat is able to Estrela et al. ACE-Inhibitor Attenuates Cisplatin Nephrotoxicity restore cell viability, and cisplatin plus enalaprilat and apstatin decreases cell viability. In the present study, we demonstrated that enalapril prevents cisplatin nephrotoxicity mainly by preventing the upregulation of B1 receptor and carboxypeptidase M and the increased concentrations of kinin peptides through aminopeptidase activity restoration.

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“…In the clinical study, the hormone replacement therapy (HRT) in hypertensive postmenopausal women decrease the serum levels of ACE activity and increase the plasma level of angiotensin II (ANG II) and bradykinin [45]. Cultured primary hypothalamic neurons of mice treated with ANG II showed a significant increase of B1R expression, an increase of oxidative stress and proinflammatory cytokines, which were prevented by pretreatment with B1R antagonist (R-715) [49]. Thus, the HRT may facilitate the kinin-kallikrein system and B1R activity.…”

Section: Discussionmentioning

confidence: 99%

Blockade of Kinin B₁receptor counteracts the depressive-like behavior and mechanical allodynia in ovariectomized mice

Maciel

Azevedo

Oliboni

et al. 2020

Preprint

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Menopause is related to a decline in ovarian estrogen production, affecting the perception of the somatosensory stimulus, changing the immune-inflammatory systems, and triggering depressive symptoms. Inhibition of kinin B1 and B2 receptors (B1R and B2R) inhibits the depressive-like behavior and mechanical allodynia induced by immune-inflammatory mediators in mice. However, there is no evidence on the role of kinin receptors in depressive-like and nociceptive behavior in female mice submitted to bilateral ovariectomy. This study shows that ovariectomized mice (OVX) developed time-related mechanical allodynia and increased immobility time in the tail suspension test (TST). The genetic deletion of B1R, or the pharmacological blockade by selective kinin B1R antagonist R-715 (acute, i.p), reduced the increase of immobility time and mechanical allodynia induced by ovariectomy. Neither genetic deletion nor pharmacological inhibition of B2R (HOE 140, i.p) prevented the behavioral changes elicited by OVX. Our data suggested a particular modulation of kinin B1R in the nociceptive and depressive-like behavior in ovariectomized mice. Selective inhibition of the B1R receptor may be a new pharmacological target for treating pain and depression symptoms in women on the perimenopause/menopause period.

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Kinin B1 Receptor Blockade Prevents Angiotensin II-induced Neuroinflammation and Oxidative Stress in Primary Hypothalamic Neurons

Cited by 25 publications

References 53 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

Angiotensin-Converting Enzyme Inhibitor Protects Against Cisplatin Nephrotoxicity by Modulating Kinin B1 Receptor Expression and Aminopeptidase P Activity in Mice

Blockade of Kinin B₁receptor counteracts the depressive-like behavior and mechanical allodynia in ovariectomized mice

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Kinin B1 Receptor Blockade Prevents Angiotensin II-induced Neuroinflammation and Oxidative Stress in Primary Hypothalamic Neurons

Cited by 25 publications

References 53 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

Angiotensin-Converting Enzyme Inhibitor Protects Against Cisplatin Nephrotoxicity by Modulating Kinin B1 Receptor Expression and Aminopeptidase P Activity in Mice

Blockade of Kinin B1receptor counteracts the depressive-like behavior and mechanical allodynia in ovariectomized mice

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Blockade of Kinin B₁receptor counteracts the depressive-like behavior and mechanical allodynia in ovariectomized mice