B2 kinin receptor overexpression rat as hereditary angioedema animal model

Abstract

Hereditary angioedema (HAE) is mainly known as an autosomal dominant disease characterized by C1 esterase inhibitor (C1-INH) quantitative (type I) or functional (type II) deficiency leading to swellings of one or more tissues. C1-INH inhibits proteases of the complement pathways, coagulation factors XI (FXI) and XII (FXII), plasma kallikrein (KK), and its deficiency results in an uncontrolled bradykinin (BK) release through KK activity, that binds to kinin B2 receptor (B2R) leading to inflammation and vasodilatation. Besides HAE types I and II, HAE without C1-INH has been widely described, which can be distinguished in presenting FXII gain of function, besides HAE forms without detected alterations. Considering that the only HAE animal model described, a C1-INH-deficiency mouse, does not show phenotypic abnormalities but increased vascular permeability, the aim of this purpose is to develop a HAE animal model of B2R overexpression. A construct which express the B2R exclusive in endothelial cells will be produced and injected in fertilized eggs transferred to foster rat mothers. The identified transgenic founder's progeny will be characterized and challenged to develop angioedema episodes. Creation of an animal that can reproduce similar human symptoms when properly challenged will allow us to develop more complexes studies around BK release pathway in HAE. (AU)