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Kidney Int. 2014 Jun;85(6):1369-81. doi: 10.1038/ki.2013.535. Epub 2014 Jan 29.

The calcium-activated chloride channel Anoctamin 1 contributes to the regulation of renal function.

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Universität Regensburg, Institute für Physiologie, Regensburg, Germany.
Departments of Anatomy, Medicine and the Cardiovascular Research Institute, University California at San Francisco, San Francisco, California, USA.
1] Universität Regensburg, Institut für Anatomie, Regensburg, Germany [2] Department of Internal Medicine D, Experimental Nephrology, Universitätklinikum Münster, Albert-Schweitzer-Campus, Münster, Germany.
Department of Internal Medicine D, Universitätklinikum Münster, Albert-Schweitzer-Campus, Münster, Germany.
Department of Urology, Universitätsklinikum Münster, Albert-Schweitzer-Campus, Münster, Germany.


The role of calcium-activated chloride channels for renal function is unknown. By immunohistochemistry we demonstrate dominant expression of the recently identified calcium-activated chloride channels, Anoctamin 1 (Ano1, TMEM16A) in human and mouse proximal tubular epithelial (PTE) cells, with some expression in podocytes and other tubular segments. Ano1-null mice had proteinuria and numerous large reabsorption vesicles in PTE cells. Selective knockout of Ano1 in podocytes (Ano1-/-/Nphs2-Cre) did not impair renal function, whereas tubular knockout in Ano1-/-/Ksp-Cre mice increased urine protein excretion and decreased urine electrolyte concentrations. Purinergic stimulation activated calcium-dependent chloride currents in isolated proximal tubule epithelial cells from wild-type but not from Ano1-/-/Ksp-Cre mice. Ano1 currents were activated by acidic pH, suggesting parallel stimulation of Ano1 chloride secretion with activation of the proton-ATPase. Lack of calcium-dependent chloride secretion in cells from Ano1-/-/Ksp-Cre mice was paralleled by attenuated proton secretion and reduced endosomal acidification, which compromised proximal tubular albumin uptake. Tubular knockout of Ano1 enhanced serum renin and aldosterone concentrations, probably leading to enhanced compensatory distal tubular reabsorption, thus maintaining normal blood pressure levels. Thus, Ano1 has a role in proximal tubular proton secretion and protein reabsorption. The results correspond to regulation of the proton-ATPase by the Ano1-homolog Ist2 in yeast.

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