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

Rohan Umesh Parekh,Srinivas Sriramula

doi:10.3390/ijms22010145

Abstract

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.

Highlights

Angiotensin converting enzyme 2 (ACE2) is well established as a critical enzyme of the renin angiotensin system, that can cleave vasoconstrictor peptide angiotensin (Ang)-II into the vasodilatory peptide Ang-(1–7) in many tissues, including heart, kidney, vasculature, and brain [1,2]
We demonstrated evidence for A Disintegrin And Metalloprotease 17 (ADAM17)-mediated ACE2 shedding in the neurons [8]
We previously demonstrated that the activity of ADAM17 is elevated during excessive glutamate stimulation, leading to ACE2 shedding in neurons [8]

Summary

Introduction

Angiotensin converting enzyme 2 (ACE2) is well established as a critical enzyme of the renin angiotensin system, that can cleave vasoconstrictor peptide angiotensin (Ang)-II into the vasodilatory peptide Ang-(1–7) in many tissues, including heart, kidney, vasculature, and brain [1,2]. ACE2 plays a major role in counterbalancing the vasoconstrictor and proliferative effects of angiotensin (Ang) II by reducing Ang II-mediated responses and increasing the vasodilatory and anti-proliferative effects of Ang-(1–7) [1]. The ACE2/Ang(1–7) pathway plays an important role in opposing the effects of Ang II and its major receptor Ang II type 1 receptor (AT1R) on pathological processes such as inflammation, oxidative stress, and neurodegeneration [1,3]. Alterations in ACE2 gene and protein expression, and activity are implicated in several cardiovascular and neurodegenerative diseases. Potential therapeutic benefits of increasing ACE2 expression or activity using recombinant human

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Conclusion