Talbi, Khaoula and Cabrita, Ines and Kraus, Andre and Hofmann, Sascha and Skoczynski, Kathrin and Kunzelmann, Karl and Buchholz, Bjoern and Schreiber, Rainer (2021) The chloride channel CFTR is not required for cyst growth in an ADPKD mouse model. FASEB JOURNAL, 35 (10): e21897. ISSN 0892-6638, 1530-6860
Full text not available from this repository. (Request a copy)Abstract
Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the development of bilateral renal cysts which enlarge continuously, leading to compression of adjacent intact nephrons. The growing cysts lead to a progressive decline in renal function. Cyst growth is driven by enhanced cell proliferation and chloride secretion into the cyst lumen. Chloride secretion is believed to occur mainly by the cAMP-activated cystic fibrosis transmembrane conductance regulator (CFTR), with some contribution by the calcium-activated chloride channel TMEM16A. However, our previous work suggested TMEM16A as a major factor for renal cyst formation. The contribution of CFTR to cyst formation has never been demonstrated in an adult ADPKD mouse model. We used mice with an inducible tubule-specific Pkd1 knockout, which consistently develop polycystic kidneys upon deletion of Pkd1. Cellular properties, ion currents, and cyst development in these mice were compared with that of mice carrying a co-deletion of Pkd1 and Cftr. Knockout of Cftr did not reveal any significant impact on cyst formation in the ADPKD mouse model. Furthermore, knockout of Cftr did not attenuate the largely augmented cell proliferation observed in Pkd1 knockout kidneys. Patch clamp analysis on primary renal epithelial cells lacking expression of Pkd1 indicated an only marginal contribution of CFTR to whole cell Cl- currents, which were clearly dominated by calcium-activated TMEM16A currents. In conclusion, CFTR does not essentially contribute to renal cyst formation in mice caused by deletion of Pkd1. Enhanced cell proliferation and chloride secretion is caused primarily by upregulation of the calcium-activated chloride channel TMEM16A.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | FLUID SECRETION; FIBROSIS; EXPRESSION; GENE; EPITHELIUM; TRANSPORT; ADPKD; CFTR; cyst growth; proliferation; TMEM16A |
| Subjects: | 500 Science > 570 Life sciences |
| Divisions: | Biology, Preclinical Medicine > Institut für Physiologie > Prof. Dr. Karl Kunzelmann |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 24 Aug 2022 13:54 |
| Last Modified: | 24 Aug 2022 13:54 |
| URI: | https://pred.uni-regensburg.de/id/eprint/46377 |
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