Proceedings of The Physiological Society

Europhysiology 2018 (London, UK) (2018) Proc Physiol Soc 41, PCA138

Poster Communications

TMEM16A activation by lipid peroxidation drives renal cyst growth

R. Schreiber1, B. Buchholz2, J. Ousingsawat1, J. Scholz2, K. Kunzelmann1

1. Institute of Physiology, University of Regensburg, Regensburg, Germany. 2. Department of Nephrology and Hypertension, Friedrich-Alexander University of Erlangen-Nürnberg, Erlangen, Germany.

In polycystic kidney disease (PKD) multiple bilateral renal cysts gradually enlarge causing a decline in renal function. Transepithelial Cl- secretion through cystic fibrosis transmembrane conductance regulator (CFTR) and TMEM16A (anoctamin 1) is known to drive cyst enlargement. Recently we found that Cl- currents by TMEM16A are not only controlled by intracellular Ca2+ levels, but also by plasma membrane phospholipids. Modifications occurring in plasma membrane phospholipids by phospholipase A2 or ROS-induced lipid peroxidation could activate TMEM16A. We therefore examined whether membrane phospholipids are oxidized in polycystic kidneys and whether this activates TMEM16A. We show that plasma membrane phospholipids in human and mouse polycystic kidneys are strongly peroxidized, probably because of regional hypoxia. MDCK cysts in vitro also demonstrated enhanced levels of reactive oxygen species (ROS), which greatly correlated with cyst volume. ROS and lipid peroxidation strongly activated TMEM16A, leading to Ca2+ store depletion. Store operated Ca2+ influx augmented activation of CFTR, the essential secretory Cl- channel known to drive cyst growth. ROS scavengers such as glutathione or the analogue of coenzyme Q10, idebenone, as well as inhibition of lipid peroxidation by ferrostatin-1 largely attenuated activation of TMEM16A and thus reduced proliferation and fluid secretion in vitro. We propose inhibition of TMEM16A by antagonizing lipid peroxidation as a novel powerful therapeutic tool to delay cyst development in PKD.

Where applicable, experiments conform with Society ethical requirements