The physiological significance of the renal tubular prorenin receptor (PRR) has been difficult to elucidate due to developmental abnormalities associated with global or renal-specific PRR knockout (KO). We recently developed an inducible renal tubule-wide PRR KO using the Pax8/LC1 transgenes and demonstrated that disruption of renal tubular PRR at 1 month of age caused no renal histological abnormalities. Here, we examined the role of renal tubular PRR in blood pressure (BP) regulation and Na⁺ excretion and investigated the signaling mechanisms by which PRR regulates Na⁺ balance. No detectable differences in BP were observed between control and PRR KO mice fed normal or low Na⁺ diets. However, compared to controls, PRR KO mice had elevated plasma renin concentration and lower cumulative Na⁺ balance with normal and low Na⁺ intake. PRR KO mice had an attenuated hypertensive response and reduced Na⁺ retention following angiotensin-II infusion. Further, PRR KO mice had significantly lower epithelial Na⁺ channel (ENaC-α) expression. Treatment with mouse prorenin increased, while PRR antagonism decreased, ENaC activity in isolated split-open collecting ducts (CD). The prorenin effect was prevented by protein kinase A and Akt inhibition, but unaffected by blockade of AT-1, ERK1/2 or p38 MAPK pathways. Taken together, these data indicate that renal tubular PRR, likely via direct prorenin/renin stimulation of PKA/Akt-dependent pathways, stimulates CD ENaC activity. Absence of renal tubular PRR promotes Na⁺ wasting and reduces the hypertensive response to Ang-II.