Hypertension induced by long-term infusion of angiotensin II (Ang II) is associated with augmented intrarenal Ang II levels to a greater extent than can be explained on the basis of the circulating Ang II levels. Although part of this augmentation is due to AT1 receptor–dependent internalization, the intracellular compartments involved in this Ang II accumulation remain unknown. In the present study, we sought to determine whether Ang II trafficking into renal cortical endosomes is increased during Ang II hypertension, and if so, whether the AT1 receptor antagonist, candesartan, prevents this accumulation. Compared with controls (n=12; 114±2 mm Hg), Ang II-infused rats (n=12; 80 ng/kg/min, SC, for 13 days) developed hypertension with systolic blood pressure rising to 185±4 mm Hg by Day 12. In Ang II hypertensive rats, plasma renin activity was suppressed, whereas plasma and kidney Ang II levels were increased by 3-fold (348±58 versus 119±16 fmol/mL) and 2-fold (399±39 versus 186±26 fmol/g). Intracellular ...

Recent studies have reported that intrarenal angiotensin II content and angiotensin II concentrations in the proximal tubular fluid and renal interstitial fluid are much greater than the circulating angiotensin II levels. These high intrarenal angiotensin II levels are responsible for regulating renal hemodynamics and tubular transport. Intrarenal angiotensin II levels have been assessed from total tissue contents as well as renal interstitial fluid and proximal tubular fluid concentrations. Total tissue contents expressed per gram of tissue weight are greater than plasma angiotensin II concentrations; tubular fluid concentrations and renal interstitial fluid concentrations are even greater in the range of 3-10 pmoles/ml. In hypertensive states, there is also an increased intracellular accumulation of angiotensin II mediated by angiotensin type 1 receptor-dependent endocytosis. The high intrarenal angiotensin II levels are also caused by the presence of angiotensinogen messenger RNA and protein in the proximal tubule cells. Furthermore, there is positive amplification by which increases in circulating angiotensin II stimulate increased production and secretion of angiotensinogen, which is also manifested as an increased urinary excretion rate. The ability of the kidney to generate high intratubular and interstitial concentrations allows the kidney to regulate intrarenal levels in accord with the homeostatic needs for the regulation of renal hemodynamics and tubular reabsorption and the regulation of sodium balance. When inappropriately stimulated, high intrarenal angiotensin II levels contribute to excessive salt and water retention, the development of hypertension, and long-term proliferative effects leading to renal injury.

Purpose of review The purpose of this review is to provide an update on the current knowledge regarding the role of the intrarenal rennin–angiotensin system (RAS) in the regulation of glomerular function including glomerular dynamics and filtration rate, glomerular permeability and structural alterations during chronic increases in intrarenal angiotensin (Ang) II. Recent findings Recent studies have continued to delineate the complex interactions among the various RAS components that participate in regulating glomerular function. Although Ang II acting on AT1 receptors remains as the predominant influence on glomerular dynamics, some of these effects are indirectly mediated by Ang II modulating the sensitivity of the macula densa tubuloglomerular feedback mechanism as well as the more recently described feedback mechanism from the connecting tubule. Interestingly, the actions of Ang II on these systems cause opposite effects on glomerular function demonstrating the complexities associated with the influences of Ang II on glomerular function. When chronically elevated, Ang II also stimulates and/or interacts with other factors, including reactive oxygen species, cytokines and growth factors and other hormones or paracrine agents, to elicit structural alterations. Summary Recent studies have provided further evidence for the presence of many components of the RAS in glomerular structures, which supports the importance of locally produced angiotensin peptides to regulate glomerular haemodynamics, filtration rate and macromolecular permeability and contribute to fibrosis and glomerular injury when inappropriately augmented.