Studies using various models of experimental hypertension have shown that subtle increases in circulating angiotensin II (Ang II) cause an augmentation of the intrarenal/intratubular renin-angiotensin system (RAS) which contributes to enhanced sodium reabsorption in proximal and distal nephron segments and the progressive development of hypertension and tissue injury. These models exhibit increases in proximal tubule angiotensinogen mRNA and protein, angiotensin converting enzyme (ACE), renin/prorenin in principal cells, and prorenin receptor (PRR) in intercalated cells of collecting ducts (CD). The intrarenal RAS activation leads to increased excretion of angiotensinogen, as well as renin and Ang II, in the urine. The chronic Ang II infused models in rats and mice have been used to show dissociation between plasma and juxtaglomerular (JG) cell renin which are suppressed, and the CD renin which is increased and has been associated with enhanced distal tubular Ang II levels and sodium reabsorption. In this particular model, principal cells of the CD secrete renin into the urine, which contribute to augment intratubular generation of Ang II in the distal nephron segments. Because plasma and JG renin are markedly suppressed, their contribution to the increased urinary renin is unlikely. Likewise, chronic Ang II infusions stimulate angiotensinogen mRNA and protein which is then secreted into the tubular lumen by the proximal tubule cells and spilled into the distal nephron segments providing substrate for Ang I formation by renin. Augmentation of CD renin secretion along with the upregulation of PRR in CD intercalated cells enhances renin/prorenin enzymatic activity. Additionally, the soluble form of PRR (sPRR) is secreted into the lumen contributing further to angiotensinogen cleavage thus making more substrate available for Ang II formation. The 2-kidney 1-clip hypertensive model has been used to discriminate between the effects of the increases in renal perfusion pressure and high intrarenal Ang II content on the stimulation of renin and ACE in the CD. In this model, both the clipped kidney and the unclipped kidney, which is subjected to the increased arterial pressure, show an increase in renin expression in CD segments indicating that the prevailing blood pressure is not directly regulating CD renin/prorenin. This model has also been important to demonstrate that enhancement of CD renin in both the clipped kidney and the unclipped kidney is associated with reciprocal changes in Ang II and Ang 1-7 content and ACE and ACE2 activities. The Ang II infused rats and the 2-kidney 1-clip hypertensive model have demonstrated that the effects of Ang II on CD renin upregulation are mainly due to direct activation of the AT1 receptors present in the distal nephron as these are blocked by AT1 receptor antagonists. The effects on CD renin upregulations are independent of sodium reabsorption or mineralocorticoid receptor activity. The Cyp1a1-Ren2 transgenic rat model of inducible ANG II-dependent hypertension has shown that stimulation of increased renin formation of non-renal origin which stimulates circulating Ang II also leads to increased CD renin levels and increased urinary excretion of angiotensinogen, renin and Ang II. These findings are consistent with the ability of elevated circulating ANG II levels, secondary to increased extrarenal renin formation, to stimulate intratubular formation of ANG II. Transgenic mouse models with lack of ACE expression and activity either systemically or within the kidney have been used to demonstrate the importance of intrarenal ACE and intrarenally formed Ang II in the development of Ang II dependent hypertension. The ability of intrarenally formed Ang II to stimulate endogenous intrarenal angiotensinogen expression and the importance of tubular AT1 receptors in the development of hypertension has been shown using mice harboring human angiotensinogen and renin transgenes that are expressed systemically or in the kidney only. Collectively, the data obtained from different experimental models of hypertension have led to the conceptual development of a robust intrarenal/intratubular RAS which, if inappropriately stimulated, contributes to an augmented tubular sodium reabsorption and the progressive development of hypertension and tissue injury.