The calcium-activated chloride channel Anoctamin 1 contributes to the regulation of renal function.
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.
Universität Regensburg, Institute für Physiologie, Regensburg, Germany.
Diana
D
Faria
Departments of Anatomy, Medicine and the Cardiovascular Research Institute, University California at San Francisco, San Francisco, California, USA.
Jason R
JR
Rock
Universität Regensburg, Institute für Physiologie, Regensburg, Germany.
Ana M
AM
Romao
Universität Regensburg, Institute für Physiologie, Regensburg, Germany.
Frank
F
Schweda
Universität Regensburg, Institute für Physiologie, Regensburg, Germany.
Sascha
S
Bandulik
1] Universität Regensburg, Institut für Anatomie, Regensburg, Germany [2] Department of Internal Medicine D, Experimental Nephrology, Universitätklinikum Münster, Albert-Schweitzer-Campus, Münster, Germany.
Ralph
R
Witzgall
Department of Internal Medicine D, Universitätklinikum Münster, Albert-Schweitzer-Campus, Münster, Germany.
Eberhard
E
Schlatter
Department of Internal Medicine D, Universitätklinikum Münster, Albert-Schweitzer-Campus, Münster, Germany.
Dirk
D
Heitzmann
Department of Internal Medicine D, Universitätklinikum Münster, Albert-Schweitzer-Campus, Münster, Germany.
Hermann
H
Pavenstädt
Department of Urology, Universitätsklinikum Münster, Albert-Schweitzer-Campus, Münster, Germany.
Edwin
E
Herrmann
Universität Regensburg, Institute für Physiologie, Regensburg, Germany.
Karl
K
Kunzelmann
Universität Regensburg, Institute für Physiologie, Regensburg, Germany.
Rainer
R
Schreiber
D000255:Adenosine Triphosphate / Q000494:pharmacology; D000450:Aldosterone / Q000097:blood; D000818:Animals; D000075369:Anoctamin-1; D002478:Cells, Cultured; D018118:Chloride Channels / Q000172:deficiency / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005838:Genotype; D006801:Humans; D006863:Hydrogen-Ion Concentration; D015640:Ion Channel Gating; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D050199:Podocytes / Q000187:drug effects / Q000378:metabolism*; D011507:Proteinuria / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D065608:Renal Reabsorption / Q000187:drug effects; D012083:Renin / Q000097:blood; D013997:Time Factors; D025262:Vacuolar Proton-Translocating ATPases / Q000378:metabolism
C476213:ANO1 protein, human; C531181:ANO1 protein, mouse; D000075369:Anoctamin-1; D018118:Chloride Channels; D009363:Neoplasm Proteins; D000450:Aldosterone; D000255:Adenosine Triphosphate; D012083:Renin; D025262:Vacuolar Proton-Translocating ATPases