title: Recent Updates on the Proximal Tubule Renin-Angiotensin System in Angiotensin II-Dependent Hypertension.
abstract: It is well recognized that the renin-angiotensin system (RAS) exists not only as circulating, paracrine (cell to cell), but also intracrine (intracellular) system. In the kidney, however, it is difficult to dissect the respective contributions of circulating RAS versus intrarenal RAS to the physiological regulation of proximal tubular Na(+) reabsorption and hypertension. Here, we review recent studies to provide an update in this research field with a focus on the proximal tubular RAS in angiotensin II (ANG II)-induced hypertension. Careful analysis of available evidence supports the hypothesis that both local synthesis or formation and AT1 (AT1a) receptor- and/or megalin-mediated uptake of angiotensinogen (AGT), ANG I and ANG II contribute to high levels of ANG II in the proximal tubules of the kidney. Under physiological conditions, nearly all major components of the RAS including AGT, prorenin, renin, ANG I, and ANG II would be filtered by the glomerulus and taken up by the proximal tubules. In ANG II-dependent hypertension, the expression of AGT, prorenin, and (pro)renin receptors, and angiotensin-converting enzyme (ACE) is upregulated rather than downregulated in the kidney. Furthermore, hypertension damages the glomerular filtration barrier, which augments the filtration of circulating AGT, prorenin, renin, ANG I, and ANG II and their uptake in the proximal tubules. Together, increased local ANG II formation and augmented uptake of circulating ANG II in the proximal tubules, via activation of AT1 (AT1a) receptors and Na(+)/H(+) exchanger 3, may provide a powerful feedforward mechanism for promoting Na(+) retention and the development of ANG II-induced hypertension.
authors.affiliation: Laboratory of Receptor and Signal Transduction, Department of Pharmacology and Toxicology, 2500 North State Street, Jackson, MS, 39216-4505, USA.
authors.forename: Xiao C
authors.initials: XC
authors.lastname: Li
authors.affiliation: Laboratory of Receptor and Signal Transduction, Department of Pharmacology and Toxicology, 2500 North State Street, Jackson, MS, 39216-4505, USA. jzhuo@umc.edu.
authors.forename: Jia L
authors.initials: JL
authors.lastname: Zhuo
mesh_terms: D000804:Angiotensin II / Q000502:physiology*; D000808:Angiotensinogen / Q000502:physiology; D000818:Animals; D005260:Female; D006801:Humans; D006973:Hypertension / Q000503:physiopathology*; D007687:Kidney Tubules, Proximal / Q000503:physiopathology*; D026561:Low Density Lipoprotein Receptor-Related Protein-2 / Q000502:physiology; D008297:Male; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000502:physiology; D012084:Renin-Angiotensin System / Q000502:physiology*; D012964:Sodium / Q000097:blood / Q000378:metabolism; D017923:Sodium-Hydrogen Exchangers / Q000502:physiology; D015854:Up-Regulation / Q000502:physiology; D025262:Vacuolar Proton-Translocating ATPases / Q000502:physiology; D000093342:Prorenin Receptor
chemical_list: C458319:ATP6AP2 protein, human; D026561:Low Density Lipoprotein Receptor-Related Protein-2; D044140:Receptor, Angiotensin, Type 1; D011956:Receptors, Cell Surface; D017923:Sodium-Hydrogen Exchangers; D000808:Angiotensinogen; D000804:Angiotensin II; D012964:Sodium; D025262:Vacuolar Proton-Translocating ATPases; D000093342:Prorenin Receptor
keywords: Angiotensin II; Hypertension; Kidney; Megalin; Proximal tubule