[38]. II-dependent hypertension. Based on a lecture given at the recent XI International Symposium on Vasoactive Peptides held in Horizonte, Brazil, this article reviews recent studies using mouse models with global, kidney- or proximal tubule-specific overexpression (knockin) or deletion (knockout) of components of the RAS or its receptors. Although much knowledges has been gained from cell- and tissue-specific transgenic or knockout models, a unifying and integrative approach is now Tariquidar (XR9576) required to better understand how the circulating and local intratubular/intracellular RAS act independently, or with other vasoactive systems, to regulate blood pressure, cardiovascular and kidney function. Introduction Since the seminal discovery of the rate-limiting enzyme renin by Robert Tigerstedt and P. G. Bergman in 1898 [1] and the landmark study of Goldblatt et al. around the role of renin in the development of 2-kidney, 1-clip hypertension in 1934 [2], the renin-angiotensin system (RAS) has since been the most extensively studied endocrine (tissue-to-tissue), paracrine (cell-to-cell) and intracrine (intracellular) hormonal system. A critical role for the RAS in the regulation of arterial blood pressure, cardiovascular and kidney function, and the development of hypertension is now firmly established from studies using genetically altered animals [3C9] and human clinical studies using the pharmacological inhibitors of the system to target this system in hypertension and other cardiovascular and kidney diseases [10C16]. The classic endocrine and paracrine paradigms as a powerful vasoconstrictor, a stimulator of the release of aldosterone, and a renal sodium-retaining hormone have led to the Ctsd one of the most successful drug discovery stories of the century, i.e., and the development of the inhibitors of angiotensin-converting enzyme (ACE) and renin, and the blockers of the type 1 angiotensin II (ANG II) (ARBs) and aldosterone receptors. Indeed, ACE and renin inhibitors, and ARBs and aldosterone receptor antagonists are the mainstays for the treatment of hypertension, stroke, heart failure, diabetic nephropathy, and other kidney diseases [10C16]. However, recent studies have also shown that this classical RAS paradigm has evolved significantly following discoveries of several new members, enzymes, or receptors of the RAS and their new functions, including prorenin receptors (PRR) [17,18], ACE2 [19,20], and ANG (1C7)/Mas receptors [21C24]. Thus, the key members of the classical RAS, Tariquidar (XR9576) including renin, ACE, ANG II and aldosterone, are no longer considered to be the only active effector molecules, but the classic renin/ACE/ANG II/AT1 receptor axis still plays a predominant role in the regulation of arterial blood pressure, cardiovascular and kidney function, and the pathogenesis of hypertension [3C9]. The nonclassical pathways, such as the prorenin/prorenin receptor (PRR)/V-ATPase axis [18,25] and the intracrine (intracellular/mitochondria/nuclear) ANG II/AT1 and AT2 receptor axis [26C28] also appear to play an important role in the long-term transcriptional responses to the RAS stimulation. Conversely, the so-called protective arms of the RAS include the ACE2/ANG 1C7/Mas receptor axis, the aminopeptidase A (APA)/ANG III/AT2 receptor axis, and the ANG IV/AT4 receptor/IRAP axis serve counteracting functions of the renin/ACE/ANG II/AT1 receptor axis [19C24]. Based on the lecture at the Tariquidar (XR9576) XI International Symposium on Vasoactive Peptides held in Belo Horizonte of Brazil in 2017, this article aims to review the new functions of intratubular and/or intracellular RAS uncovered using genetically altered animals with either overexpression or deficiency of one key enzyme, ANG peptide, or receptor of the RAS in the kidney, and discuss their physiological relevance and perspectives. Intratubular RAS in the kidney: current consensus and debates Most Tariquidar (XR9576) of the investigators agree that the RAS (RAS) plays an indispensable role in the cardiovascular and renal regulation, normal blood pressure homeostasis, and the pathogenesis of hypertension [29C35]. There is also a general consensus that both circulating (endocrine) and local (paracrine) RAS act interactively to regulate vascular and sympathetic tones, renal pressure natriuresis response, and salt and water balance [29C35]. However, there are continuous debates with respect to: a) the origins of the intratubular and/or intracellular RAS [30,36C39]; b) the relative contributions of the circulating versus intrarenal RAS to the regulation of renal function [38C41]; Tariquidar (XR9576) c) the functions of intratubular RAS to the normal control of blood pressure and the development of ANG II-induced hypertension [29C31,42]; and.