Angiotensin-II-Type-1a Receptor (AT1aR) and Renal K+ Wasting during Overnight Low-Na+ Intake.

ABSTRACT

BACKGROUND: Chronic Angiotensin-II (Ang-II) perfusion stimulates Kir4.1/Kir5.1 of the DCT via angiotensin-II-type-1a-receptor (AT1aR) and low-sodium-intake also stimulates Kir4.1/Kir5.1. However, it is not explored the role of AT1aR in mediating the effect of LS on Kir4.1/Kir5.1. METHODS: We used patch-clamp-technique to examine Kir4.1/Kir5.1 activity of the DCT, employed immunoblotting to examine NCC expression/activity, and used in vivo perfusion-technique to measure renal-Na+ and renal-K+-excretion in control, kidney-tubule-specific-AT1aR-knockout (Ks-AT1aR-KO) and DCT-specific-AT1aR-knockout mice (DCT-AT1aR- KO). RESULTS: Ang-II acutely stimulated 40-pS-K+ channel (Kir4.1/Kir5.1-heterotetramer), increased whole-cell Kir4.1/Kir5.1-mediated K+-currents and the negativity of DCT-membrane-potential only in late-DCT2 but not in early-DCT. Acute Ang-II increased thiazide-induced renal Na+-excretion (ENa). The effect of Ang-II on Kir4.1/Kir5.1 and HCTZ-induced-ENa was absent in Ks-AT1aR-KO mice. Overnight-low-salt stimulated the expression of Agtr1a mRNA in DCT, increased whole-cell Kir4.1/Kir5.1-mediated K+-currents in late-DCT, hyperpolarized late-DCT membrane, augmented the expression of phosphor-Na-Cl-cotransporter (pNCC) and enhanced thiazide-induced renal-ENa in the control mice. However, the effect of overnight-low-salt on Kir4.1/Kir5.1-activity, DCT membrane potential and NCC activity/expression was abolished in DCT-AT1aR-KO or Ks-AT1aR-KO mice. Overnight-low-salt had no effect on baseline renal K+-excretion (EK) and plasma K+-concentrations in the control mice but it increased baseline renal-EK and decreased plasma K+-concentrations in DCT-AT1aR-KO or in Ks-AT1aR-KO mice. CONCLUSIONS: Acute Ang-II or overnight-LS stimulated Kir4.1/Kir5.1 in late-DCT and that AT1aR was responsible for acute Ang-II or overnight-low-salt-induced stimulation of Kir4.1/Kir5.1 and NCC. AT1aR of the DCT plays a role in maintaining adequate baseline renal-EK and plasma K+ concentrations during overnight-LS.