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Differential Localization of Vacuolar H+-ATPases Containing a1, a2, a3, or a4 (ATP6V0A1-4) Subunit Isoforms Along the NephronSchulz N. · Dave M.H. · Stehberger P.A. · Chau T.C. · Wagner C.A.
Institute of Physiology and Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich Corresponding Author
Carsten A. Wagner
Institute of Physiology, University of Zurich
Winterthurerstr. 190, CH-8057 Zurich (Switzerland)
Tel. +41-1-6350659, Fax: +41-1-635814
Vacuolar H+-ATPase are multi-subunit containing pumps important for several processes along the nephron such as receptor mediated endocytosis, acidification of intracellular organelles, bicarbonate reabsorption and secretion, and H+- extrusion. Mutations in the human a4 (ATP6V0A4) subunit cause distal renal tubular acidosis (dRTA). There are 4 known isoforms of the ‘a’ subunit (a1-a4). Here we investigated the expression and localization of all four isoforms in mouse kidney. Real-time PCR detected mRNAs encoding all four ‘a’ isoforms in mouse kidney with a relative abundance in the following order: a4>a2=a1>a3. Immunolocalization demonstrated expression of all ‘a’ subunits in the proximal tubule and in the intercalated cells of the collecting system. In intercalated cells a1 and a4 isoforms appeared on both the apical and basolateral side and were expressed in all subtypes of intercalated cells. In contrast, a2, and a3 were only found in the apical membrane. a1 and a4 were colocalized in the same cells with AE1 or pendrin, whereas a2 was only found in AE1 positive cells but absent from pendrin expressing intercalated cells. These results suggest that vacuolar H+-ATPases containing different ‘a’ isoforms may serve specific and distinct functions and may help explaining why loss of the a4 isoform causes only dRTA without an apparent defect in the proximal tubule.
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