(Pro)renin receptor (PRR) is highly expressed in the distal nephron with unclear functional implication. The present study was conducted to explore a potential role of renal PRR during high K+ (HK) loading. In normal Sprague-Dawley rats, a 1-week HK intake increased renal expression of full-length PRR and urinary excretion of soluble PRR (sPRR). Administration of PRO20, a decoy peptide antagonist of PRR, to K+-loaded animals elevated plasma K+ level and decreased urinary K+ excretion, accompanied with suppressed aldosterone excretion. HK downregulated Na+-Cl- cotransporter (NCC) expression but upregulated CYP11B2 (cytochrome P450, family 11, subfamily B, polypeptide 2), renal outer medullary K+ channel (ROMK), calcium-activated potassium channel subunit alpha-1 (α-BK), α-Na+-K+-ATPase (α-NKA), and epithelial Na+ channel subunit beta (β-ENaC), all of which were blunted by PRO20. Following HK, urinary but not plasma renin was upregulated, which was blunted by PRO20. The same experiments performed using adrenalectomized (ADX) rats yielded similar results. Interestingly, spironolactone treatment in HK-loaded ADX rats attenuated kaliuresis but promoted natriuresis associated with the suppressed responses of β-ENaC, α-NKA, ROMK, and α-BK protein expression. Taken together, we discovered a novel role of renal PRR in regulation of K+ homeostasis that is likely through a local mechanism involving intrarenal renin-angiotensin-aldosterone system and coordinated regulation of membrane Na+ and K+ transporting proteins.