Based on recent studies from our and other’s laboratories, we hypothesize that the intratubular, intracellular, and mitochondrial Ang II/AT1a/NHE3 signaling pathways in the proximal tubules of the kidney may serve as new renal mechanisms and therapeutic targets at least in hypertension and kidney diseases associated with activation of the intratubular renin-angiotensin system. Here, REN is linked to kidney disorder.