Glucose promotes secretion-dependent renal cyst growth.
Polycystic kidney diseases are characterized by the development of numerous bilateral renal cysts that continuously enlarge resulting in a decline of kidney function due to compression of intact nephrons. Cyst growth is driven by transepithelial chloride secretion which depends on both intracellular cAMP and calcium. Mechanisms that are involved in the regulation of the underlying secretory pathways remain incompletely understood. Here we show that glucose concentration has a strong impact on cyst growth of renal tubular cells within a collagen matrix as well as in embryonic kidneys deficient or competent for Pkd1. Glucose-dependent cyst growth correlates with the transcriptional induction of the calcium-activated chloride channel anoctamin 1 (ANO1) and its increased expression in the apical membrane of cyst-forming cells. Inhibition of ANO1 with the specific inhibitor CaCCinh-AO1 significantly decreases glucose-dependent cyst growth in both models. Ussing chamber analyses revealed increased apical chloride secretion of renal tubular cells upon exposure to high glucose medium which can also be inhibited by the use of CaCCinh-AO1. These data suggest that glycemic control may help to reduce renal cyst growth in patients with polycystic kidney disease.


CONCLUSIONS
Renal cyst growth depends on glucose concentration in two in vitro cyst models. High glucose leads to upregulation of the calcium-activated chloride channel ANO1. High glucose promotes calcium-activated chloride secretion via ANO1. Glucose-dependent secretion can be inhibited by a specific inhibitor of ANO1.
Department of Nephrology and Hypertension, Friedrich-Alexander-University Erlangen-Nürnberg, Ulmenweg 18, 91054, Erlangen, Germany.
Andre
A
Kraus
Department of Nephrology and Hypertension, Friedrich-Alexander-University Erlangen-Nürnberg, Ulmenweg 18, 91054, Erlangen, Germany.
Gunnar
G
Schley
Department of Physiology, University of Regensburg, 93053, Regensburg, Germany.
Karl
K
Kunzelmann
Department of Physiology, University of Regensburg, 93053, Regensburg, Germany.
Rainer
R
Schreiber
Department of Human Genetics, Leiden University Medical Centre, 2333 ZA, Leiden, Netherlands.
Dorien J M
DJ
Peters
Department of Biology, Friedrich-Alexander-University Erlangen-Nürnberg, 91054, Erlangen, Germany.
Ruth
R
Stadler
Department of Nephrology and Hypertension, Friedrich-Alexander-University Erlangen-Nürnberg, Ulmenweg 18, 91054, Erlangen, Germany.
Kai-Uwe
KU
Eckardt
Department of Nephrology and Hypertension, Friedrich-Alexander-University Erlangen-Nürnberg, Ulmenweg 18, 91054, Erlangen, Germany. Bjoern.Buchholz@uk-erlangen.de.
Bjoern
B
Buchholz
D000818:Animals; D000075369:Anoctamin-1; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D018118:Chloride Channels / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D002712:Chlorides / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism; D003560:Cysts / Q000473:pathology*; D004285:Dogs; D005947:Glucose / Q000494:pharmacology*; D007684:Kidney Tubules / Q000166:cytology / Q000196:embryology / Q000473:pathology*; D061985:Madin Darby Canine Kidney Cells; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016891:Polycystic Kidney, Autosomal Dominant / Q000473:pathology*; D050396:TRPP Cation Channels / Q000235:genetics*; D015533:Transcriptional Activation / Q000235:genetics
D000075369:Anoctamin-1; D002118:Calcium; D018118:Chloride Channels; D002712:Chlorides; D000242:Cyclic AMP; D005947:Glucose; D050396:TRPP Cation Channels; C531181:ANO1 protein, mouse
Anoctamin 1; Chloride secretion; Cyst growth; Diabetes mellitus type 2; Glucose; Polycystic kidney disease