Abstract

Activation of renin–angiotensin system (RAS) plays a role in bone deterioration associated with bone metabolic disorders, via increased Angiotensin II (AngII) targeting Angiotensin II type 1 receptor/Angiotensin II type 2 receptor (AT1R/AT2R). Despite the wide data availability, the RAS role remains controversial. This study analyzes the feasibility of using the embryonic chick femur organotypic model to address AngII/AT1R/AT2R axis in bone, which is an application not yet considered. Embryonic day-11 femurs were cultured ex vivo for 11 days in three settings: basal conditions, exposure to AngII, and modulation of AngII effects by prior receptor blockade, i.e., AT1R, AT2R, and AT1R + AT2R. Tissue response was evaluated by combining µCT and histological analysis. Basal-cultured femurs expressed components of RAS, namely ACE, AT1R, AT2R, and MasR (qPCR analysis). Bone formation occurred in the diaphyseal region in all conditions. In basal-cultured femurs, AT1R blocking increased Bone Surface/Bone Volume (BS/BV), whereas Bone Volume/Tissue Volume (BV/TV) decreased with AT2R or AT1R + AT2R blockade. Exposure to AngII greatly decreased BV/TV compared to basal conditions. Receptor blockade prior to AngII addition prevented this effect, i.e., AT1R blockade induced BV/TV, whereas blocking AT2R caused lower BV/TV increase but greater BS/BV; AT1R + AT2R blockade also improved BV/TV. Concluding, the embryonic chick femur model was sensitive to three relevant RAS research setups, proving its usefulness to address AngII/AT1R/AT2R axis in bone both in basal and activated conditions.

Highlights

  • The endocrine renin–angiotensin system (RAS) has a key role in the control of blood pressure, blood volume, and fluid balance, and its activation participates in the development and/or progression of cardiovascular, renal, and metabolic diseases [1]

  • Considering the above observations, this study aims to analyze the feasibility of the ex vivo embryonic chick femur model to address the Angiotensin II (AngII)/AT1R/AT2R axis and the possibility of its modulation, which is an application tool that has not yet been investigated

  • ED11 femurs cultured ex vivo in basal conditions for 11 days were analyzed for the presence of genes coding for RAS components, as this model has not been previously searched for this application

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Summary

Introduction

The endocrine renin–angiotensin system (RAS) has a key role in the control of blood pressure, blood volume, and fluid balance, and its activation participates in the development and/or progression of cardiovascular, renal, and metabolic diseases [1]. In this system, angiotensinogen (AGT) synthesized and released from the liver is converted to angiotensin I (AngI) by renin, which is released from the juxtaglomerular cells of the kidney [2]. The angiotensin-converting enzyme (ACE) activates AngI to AngII, which attains high levels on the vasculature endothelial cell surface [2]. The RAS branch mediated by Ang, formed by the cleavage of AngII by ACE2, appears to have modulatory effects on the AngII-mediated

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