The presence of receptors for angiotensin II (AII) on the luminal membranes of various nephron segments has been well established for many decades.1,2 Originally their function remained unclear because tubular fluid AII concentrations were thought to be quite low due to the presence of various degrading enzymes on the brush border of proximal tubular cells. However, a series of reports in the 1990s demonstrated that the proximal tubular concentrations of AI and AII are in the nanomolar range and much higher than can be explained by tubular fluid reabsorption or equilibration with the circulating levels. 3,4 These findings led to a paradigm shift in our concepts regarding the role of luminal AII receptors in various nephron segments, and it is now well accepted that intraluminal AII and other angiotensin peptides exert various actions on transport systems in essentially all nephron segments predominantly through activation of AT1 receptors. 5-10In further studies, proximal tubular fluid samples were incubated with excess renin to determine substrate availability. The resultant AI concentrations demonstrated that the proximal tubular fluid angiotensinogen (AGT) concentrations are also very high 11 and greater than the circulating concentrations, indicating that it is unlikely the tubular AGT concentrations are derived from filtered AGT, in particular considering the limited permeability of the AGT because of its large size.11 Using in situ perfusion of proximal tubules with artificial tubular fluid with the delivery of filtrate blocked, Braam et al.4 collected the tubular fluid from downstream segments and found these also had elevated AII concentrations in the nanomolar range, supporting tubular secretion of AII or its precursors. Studies on isolated perfused tubules from S2 segments indicated that AII is produced intracellularly and secreted preformed into the tubular lumen, supporting the presence of intact AGT in isolated proximal tubule segments.12 These findings, along with clear evidence for the presence of AGT mRNA and protein in proximal tubular cells, [13][14][15] provided the foundation for the concept that the intratubular AII concentrations are derived primarily from locally synthesized substrate. The local production of AGT in the proximal tubule was supported by Terada et al., 14 who demonstrated the presence of a large signal for AGTmRNA in microdissected proximal convoluted and straight tubules. In vitro studies have also consistently demonstrated mRNA encoding AGT in proximal tubular cell lines extracted from proximal tubule segments.15,16 However, Pohl et al. 17 recently reported predominant localization of mRNA encoding AGT to S3 segments.The findings of kidney tubular mRNA encoding AGT notwithstanding, the kidney's ability to produce AGT is dwarfed by that of the liver, the organ primarily responsible for the maintenance of circulating AGT concentrations. In addition, it is well recognized that filtered AGT can be taken up by proximal tubule scavenger receptors such as megalin and cubilin, ...