Figure 10.

A cell scheme illustrates the role of Kir4.1/Kir5.1 in mediating the effect of Nedd4-2 on thiazide-sensitive NCC. The inhibition of Kir4.1/Kir5.1 activity by Nedd4-2 should depolarize the DCT membrane voltage (V). A decrease in the cell negativity reduces the driving force for Cl⁻ exit by basolateral Cl⁻ channels, thereby increasing intracellular Cl⁻ (Cl⁻_i), which inhibits WNK and SPAK. This leads to inhibition of NCC phosphorylation and activity. Nedd4-2 is expected to facilitate the degradation of non-pNCC. In addition, Nedd4-2 also regulates NCC retrieval from the apical membrane of the DCT by Kir4.1-indipendent mechanism (blue arrow). The dotted line indicates the inhibition.