Abstract P109: Collecting Duct Renin and Aldosterone Regulate Potassium Homeostasis

The kalliuric action of the renin-angiotensin-aldosterone system (RAAS) is well established as highlighted by hyperkaliemia side effect of RAAS inhibitors but such action is usually ascribed to systemic RAAS. The present study attempted to address the involvement of intrarenal RAAS in K + homeostasis with emphasis on locally generated renin and aldosterone (Aldo) within the collecting duct (CD). In normal C57BL/6 mice, a 1-wk high K + (HK) intake (5% KCl in diet) induced parallel increases in renal prorenin (cortex: 298.8%; medulla: 323.8%) assessed by immunoblotting, and urinary prorenin/renin content (URC) (2.5-fold) assessed by ELISA, and urinary renin activity (URA) (1.5-fold), contrasting to suppressed plasma prorenin/renin concentration (by 25.6%) and renin activity (by 61.6%). Following 1-wk HK loading, mice lacking renin in the CD (CD renin KO) had decreased urinary K + excretion (by 20.2%) and elevated plasma K + level (KO+HK: 4.35 ± 0.14 vs. Floxed+HK: 3.89 ± 0.04 mM, P <0.01), accompanied with a reduction of URC (by 40%), URA (by 58.5%), urinary free and total Aldo excretion (by 50.6% and 36.6%, respectively), and kidney cortical and medullary Aldo (by 33.5% and 49.9%, respectively), without affecting plasma Aldo or renin levels. HK upregulated renal protein expression of Aldo synthase CYP11B2 (cortical: 133.4%, medullary: 221.5%), renal outer medullary K + channel (ROMK) (146.4%), calcium-activated potassium channel subunit alpha-1 (α-BK) (160.9%), α-Na + -K + -ATPase (155.8%), β-ENaC (165.1%), and cleaved-γ-ENaC (1800%), all of which were significantly blunted in CD renin KO mice (by 25-75%). We have developed an inducible renal tubule-wide CYP11B2 KO using the Pax8/LC1 transgenes (termed as RT CYP11B2 KO). While the homozygous deletion is lethal, the heterozygous mice exhibited normal development and were subjected to 3-day HK. K + -loaded RT CYP11B2 KO mice had decreased urinary K + excretion (by 30.5%) and hyperkalemia (KO+HK: 4.63 ± 0.05 vs . Floxed+HK: 3.98 ± 0.09 mM, P <0.01), accompanied with a reduction of urinary free and total Aldo excretion (by 20.4% and 34.4%, respectively) without affecting plasma Aldo levels. Taken together, these results support a local action of CD renin and Aldo in regulation of K + homeostasis.