Abstract
Renin-angiotensin system (RAS) systemically or locally collaborates with tissue homeostasis, growth and development, which has been extensively studied for its pharmacological implications. This study was primarily aimed at finding and characterizing local RAS in rat parotid, sublingual and submandibular glands. It was also hypothesized that vasoactive drugs could affect the expression of RAS targets, as well as saliva flow and its composition. Therefore, another objective of this study was to compare the effects of losartan (angiotensin II receptor blocker) and isoproterenol (β-adrenergic receptor agonist). Forty-one Wistar rats were divided into three groups and administered a daily intraperitoneal dose of saline, losartan or isoproterenol solutions for one week. The following RAS targets were studied using qPCR: renin (REN), angiotensinogen (AGT), angiotensin converting enzyme (ACE), ACE-2, elastase-2 (ELA-2), AT1-a and MAS receptors, using RPL-13 as a reference gene. Morphology of glands was analyzed by immunohistochemistry using REN, ACE, ACE-2, AT1, AT2 and MAS antibodies. The volume and total protein content of saliva were measured. Our results revealed that ACE, ACE-2, AT1-a, AT2 and MAS receptors were expressed in all salivary gland samples, but REN and ELA-2 were absent. Losartan decreased mRNA expression of RAS targets in parotid (MAS) and submandibular glands (ACE and both AT receptors), without affecting morphological alterations, and significantly decreased saliva and total protein secretions. Isoproterenol treatment affected gene expression profiles in parotid (ACE, ACE-2, AT1-a, MAS, AGT), and submandibular (ACE, AT2, AGT) glands, thus promoting acinar hypertrophy in serous acini, without significant changes in salivary flow or total protein content. These drugs affected mainly acini, followed by duct systems and myoepithelial cells, whereas blood vessels were not affected. In conclusion, there is a local RAS in major rat salivary glands and losartan, an angiotensin II receptor blocker, affected not only the RAS-target gene expression but also decreased salivary flow and total protein content.
Highlights
The description of the Renin-angiotensin system (RAS) would allow an improved understanding of homeostatic regulatory mechanisms, involving primarily vasodilation, water intake and sodium balance
All the glands used in this study did not express the targets of REN and ELA-2; the expression of the targets angiotensin converting enzyme (ACE), ACE-2, AGT, angiotensin type 1 receptors (AT1)-a, AT2 and MAS was detected in all the samples with characteristic profiles in each gland
Our data indicate that losartan treatment decreased the MAS expression, but the other targets showed no statistical differences when compared with saline as control (Fig 2)
Summary
The description of the Renin-angiotensin system (RAS) would allow an improved understanding of homeostatic regulatory mechanisms, involving primarily vasodilation, water intake and sodium balance. The RAS classically works through the following cascade: renin (REN, originated from the juxtaglomerular cells of the kidney) cleaves angiotensinogen (AGT, a protein produced by the liver) into angiotensin-1 (Ang I: Asp1-Arg2-Val3-Tyr4-Ile5-His6-Pro7-Phe8His9-Leu). Angiotensin converting enzyme (ACE, obtained from lungs) cleaves the Phe8-His bond to produce the vasoactive octapeptide angiotensin-2 (Ang II: Asp1-Arg2-Val3Tyr4-Ile5-His6-Pro7-Phe). Ang II binds to angiotensin type 1 receptors (AT1) leading to vasoconstriction, aldosterone secretion, fibrosis, proliferation, oxidative stress and inflammation among others, which have been described previously [1,2]. Angiotensin-1-7 (Ang 1–7: Asp1-Arg2-Val3-Tyr4-Ile5-His6-Pro7) binds to MAS receptors (MAS) which has vasodilatation, antiproliferative, antithrombotic and antifibrotic effects [3,4]. 37 gene products have been described as an extended RAS [3]
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