Increased blood pressure and water intake in transgenic mice expressing rat tonin in the brain

Abstract

Tonin is a serine proteinase of the kallikrein family that can produce angiotensin II directly from angiotensinogen. To clarify the importance of this enzyme for central nervous control of the cardiovascular system, we generated transgenic mice, TGM(rTon), that express rat tonin in astrocytes. These mice present high levels of tonin mRNA and activity specifically in the brain. As a consequence, TGM(rTon) develop increased blood pressure and water intake. Lisinopril, an ACE inhibitor, is less hypotensive for transgenic mice than for control animals. The AT(1) receptor antagonist candesartan equally lowers blood pressure in transgenic and in control mice. Plasma angiotensin II, but not angiotensin I, is increased in TGM(rTon) compared to the wild type, suggesting release of the peptide from the brain into the circulation. However, AT(1) receptors are desensitized in this transgenic model, as demonstrated by a blunted pressor response to intravenous application of angiotensin II. In conclusion, tonin in the brain may represent an alternative pathway for angiotensin II generation with effects on the cardiovascular system.

Characterization of the renal renin-angiotensin system in transgenic mice that express rat tonin

“…27 The focus of our work was to study RAS in the kidney. The early controversy on the novel concept of tissue RAS has been based on the question of local synthesis vs uptake from the circulation.…”

“…Transgenic TGM`(rTon) mice were obtained by microinjection of the transgene into zygotes as described by Cardoso et al (2010). 27 Total RNA was extracted from the submandibular gland of Sprague-Dawley (SD) rats using Trizol (Invitrogen) according to the manufacturer's protocol.…”

“…The authors observed that tonin is able to generate Ang II in the isolated heart, and the cardiovascular response induced by tonin was completely blocked by candesartan, an indication that the action of Ang II on the AT 1 receptor is the major mechanism of the heart effects. 26 In order to clarify the importance of tonin for the cardiovascular system, Cardoso et al (2010) 27 generated transgenic mice that express rat tonin, the TGM(rTon). These mice present high levels of tonin messenger RNA (mRNA) and activity specifically in the brain.…”

“…Cardoso and collaborators concluded that tonin in the brain may represent an alternative pathway to generate Ang II with effects on the cardiovascular system. 27 Recently, our group generated a second lineage of transgenic mice (TGM`(rTon)) that also express rat tonin in many tissues of cardiovascular importance. More recently, our group demonstrated for the first time that the systemic antinociceptive effects in the TGM`(rTon) are blocked, at least in part, by losartan and A-779, suggesting that Ang II produced in these transgenic mice may be involved with antinociception via the AT 1 receptor, while Ang(1-7) induces its effects via the Mas receptor.…”

The 3rd International Symposium on Kallikreins and Kallikrein-Related Peptidases

“…This is reflected by several articles in the present highlight issue, including a review on the role of KLK1 in various types of diseases and wound healing , the presentation of a protein network linking the kallikrein-kinin and renin-angiotensin systems developed by employing threedimensional protein-protein interaction databases (Stoka and Turk, 2010), and the analysis of transgenic mice expressing rat tonin, the homolog of KLK2, in the brain (Cardoso et al, 2010). In the case of KLK1 and KLK8, knockout mouse models have also been utilized to elucidate their physiological functions.…”