Analysis of abnormal chloride transport in the pathogenesis of renal electrolyte disorders

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1) Pseudohypoaldosteronism type II (PHAII) is an autosomal-dominant disorder characterized by hyperkalemia, acidosis, and hypertension. Studies of monogenetic hypertensive diseases such as PHAII will provide insight into the mechanisms underlying blood pressure regulation. We clarified the pathogenesis of PHAII by generating Wnk4^<561A> knockin mice, an ideal mouse model of PHAII. We clearly showed that the major pathogenesis of PHAII is the activation of the phosphorylation cascade of the WNK4-OSR1/SPAK-NaCl cotransporter (NCC).2) CIC-K chloride channels belong to the CLC chloride channel family and play an important role in transepithelial chloride transport in the kidney. To be functional, CIC-K channels need to be translocated to the plasma membranes after synthesis : the translocation requires the binding to its b-subunit, barttin. The binding interaction between barttin and CIC-K channels has not been characterized, although the crystal structure of CLC was resolved. In the present study, we sought to clarify the binding sites of barttin in CIC-K2 by co-immunoprecipitation and immunofluorescence microscopy using various CIC-K2 mutants. We found that barttin was able to bind to the domains that constitute the outer lateral surfaces of CIC-K2. This information regarding the binding sites will be useful for designing a new class of diuretics or anti-hypertensive agents that inhibit the interaction of CIC-K and barttin.