Specific examples include 2 kidney, 1 clip (2K1C) Gold-blatt hypertension, Ang II-infused hypertension, the transgenic rat (TGR) (mRen2) model harboring an extra renin gene in its genome, the remnant kidney model produced by unilateral nephrectomy plus ligation of arterial branches in the remaining kidney, and several mouse models that overexpress renin or angiotensinogen (AGT). The important role of the RAS is also supported by studies using various experimental models of hypertension having an overactive RAS. Varying degrees of reduced renal function have been found in many hypertensive patients associated with inappropriate activation of the RAS as reflected by their responsiveness to angiotensin-converting enzyme (ACE) inhibitors or angiotensin II (Ang II) receptor blockers, even when plasma renin levels are not elevated. Regardless of the mechanism responsible for an over-active intrarenal RAS, the consequent impairment in sodium excretory capability contributes to the development of hypertension. In addition to sodium and fluid retention and progressive hypertension, there are critical long-term consequences of an inappropriately elevated RAS coexisting with hypertension, which lead to proliferative responses and vascular, glomerular, and tubular interstitial injury, and fibrosis. Indeed, there is growing recognition that inappropriate activation of the intrarenal RAS limits the capability of the kidney to maintain sodium balance at normal arterial pressures and is an important cause of hypertension. Emphasis in this article is on the renal RAS because of its unique significance in regulating sodium balance and thus long-term arterial pressure, and its role in the progression of renal diseases. There has been a paradigm shift in recent years from a focus primarily on the role of the systemic renin-angiotensin system (RAS) in the regulation of arterial pressure and in the pathophysiology of hypertension, to an emphasis on the changes in the components of the RAS at the tissue level in various organs. The augmentation of intrarenal Ang II provides the basis for sustained actions on renal function, sodium excretion, and maintenance of hypertension. The increased urinary AGT indicates spillover of AGT into distal nephron segments supporting enhanced distal Ang II formation and sodium reabsorption. The increased intrarenal AGT production is associated with increased intrarenal and intracellular Ang II contents and urinary AGT excretion rates. Ang II exerts a positive feedback action on intrarenal angiotensinogen (AGT) mRNA and protein. In Ang II-dependent hypertension, Ang II is internalized via an AT1 receptor mechanism, but there is also sustained intrarenal production of Ang II. Augmentation of intrarenal Ang II occurs by several processes, leading to levels much greater than can be explained from the circulating levels. Elevations in intrarenal angiotensin II (Ang II) cause reductions in renal function and sodium excretion that contribute to progressive hypertension and lead to renal and vascular injury.
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