Cabrita, Ines and Kraus, Andre and Scholz, Julia Katharina and Skoczynski, Kathrin and Schreiber, Rainer and Kunzelmann, Karl and Buchholz, Bjoern (2020) Cyst growth in ADPKD is prevented by pharmacological and genetic inhibition of TMEM16A in vivo. NATURE COMMUNICATIONS, 11 (1): 4320. ISSN 2041-1723,
Full text not available from this repository. (Request a copy)Abstract
In autosomal dominant polycystic kidney disease (ADPKD) multiple bilateral renal cysts gradually enlarge, leading to a decline in renal function. Transepithelial chloride secretion through cystic fibrosis transmembrane conductance regulator (CFTR) and TMEM16A (anoctamin 1) are known to drive cyst enlargement. Here we demonstrate that loss of Pkd1 increased expression of TMEM16A and CFTR and Cl- secretion in murine kidneys, with TMEM16A essentially contributing to cyst growth. Upregulated TMEM16A enhanced intracellular Ca2+ signaling and proliferation of Pkd1-deficient renal epithelial cells. In contrast, increase in Ca2+ signaling, cell proliferation and CFTR expression was not observed in Pkd1/Tmem16a double knockout mice. Knockout of Tmeml6a or inhibition of TMEM16A in vivo by the FDA-approved drugs niclosamide and benzbromarone, as well as the TMEM16A-specific inhibitor Ani9 largely reduced cyst enlargement and abnormal cyst cell proliferation. The present data establish a therapeutic concept for the treatment of ADPKD.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | KIDNEY-DISEASE; ANO1; CFTR; SECRETION; PROLIFERATION; ACTIVATION; EXPRESSION; |
| Subjects: | 500 Science > 570 Life sciences |
| Divisions: | Biology, Preclinical Medicine > Institut für Physiologie > Prof. Dr. Karl Kunzelmann |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 15 Mar 2021 13:10 |
| Last Modified: | 15 Mar 2021 13:10 |
| URI: | https://pred.uni-regensburg.de/id/eprint/43971 |
Actions (login required)
 |
View Item |
