The Intratubular and Intracrine Renin-Angiotensin System in the Proximal Tubules of the Kidney and Its Roles in Angiotensin II-Induced Hypertension

Abstract

The kidney plays a fundamental role in the physiological regulation of basal blood pressure and the development of hypertension. Although the mechanisms underlying hypertension are very complex, the renin-angiotensin system (RAS) in the kidney, especially intratubular and intracellular RAS, undoubtedly plays a critical role in maintaining basal blood pressure homeostasis and the development of angiotensin II (ANG II)-dependent hypertension. In the proximal tubules, ANG II activates two G protein-coupled receptors, AT 1 and AT 2 , to exert powerful effects to regulate proximal tubular sodium and fluid reabsorption by activating cell surface as well as intracellular AT 1 receptors. Increased production and actions of ANG II in the proximal tubules may cause salt and fluid retention, impair the pressure-natriuresis response, and consequently increase blood pressure in hypertension. The objectives of this chapter are to critically review and discuss our current understanding of intratubular and intracellular RAS in the kidney, and their contributions to basal blood pressure homeostasis and the development of ANG II-dependent hypertension. The new knowledge will likely help uncover novel renal mechanisms of hypertension, and develop kidney-or proximal tubule-specific strategies or drugs to prevent and treat hypertension in humans.

Impact of angiotensin-receptor blockers on intrarenal renin-angiotensin system activity in hypertension: A PK/PD modelling study

“…However, a decoupling of the two RAS has been observed in various experimental models of hypertension, including: Ang II-induced hypertensive rats (Zou et al, 1996), two-kidney, one-clip Goldblatt hypertensive rats (Cervenka et al, 1999), salt-sensitive rats (Wu et al, 2014), and spontaneously hypertensive rats (Takenaka et al, 1990). In Ang II-induced hypertension in particular, there is a progressive rise in intrarenal Ang II that cannot be explained on the basis of equilibration with plasma Ang II concentrations ([Ang II]) (Zou et al, 1996;Ellis et al, 2012;Gonzalez-Villalobos et al, 2008;Li et al, 2019). This response is prevented by treatment with angiotensinreceptor blockers (ARBs), a common anti-hypertensive medication that targets the RAS by binding to and blocking AT1Rs.…”