Cytosolic phospholipase A 2 regulates lipid homeostasis under osmotic stress through PPARγ

PARRA, LEANDRO GASTÓN; ERJAVEC, LUCIANA CECILIA; CASALI, CECILIA IRENE; ZERPA VELAZQUEZ, ANDREA; WEBER, KAREN; SETTON?AVRUJ, CLARA PATRICIA; FERNÁNDEZ TOME, MARÍA DEL CARMEN

FEBS JOURNAL

WILEY-BLACKWELL PUBLISHING, INC

Año: 2023

1742-464X

Physiologically, renal medullary cells are surrounded by a hyperosmolar inter- stitium. However, different pathological situations can induce abrupt changes in environmental osmolality, causing cell stress. Therefore, renal cells must adapt to survive in this new condition. We previously demonstrated that, among the mechanisms involved in osmoprotection, renal cells upregulate tri- glyceride biosynthesis (which helps preserve glycerophospholipid synthesis and membrane homeostasis) and cyclooxygenase-2 (which generates prostaglandins from arachidonic acid) to maintain lipid metabolism in renal tissue. Herein, we evaluated whether hyperosmolality modulates phospholipase A2 (PLA2) activ- ity, leading to arachidonic acid release from membrane glycerophospholipid, and investigated its possible role in hyperosmolality-induced triglyceride syn- thesis and accumulation. We found that hyperosmolality induced PLA2 expres- sion and activity in Madin-Darby canine kidney cells. Cytosolic PLA2 (cPLA2) inhibition, but not secreted or calcium-independent PLA2 (sPLA2 or iPLA2, respectively), prevented triglyceride synthesis and reduced cell survival. Inhibi- tion of prostaglandin synthesis with indomethacin not only failed to prevent hyperosmolality-induced triglyceride synthesis but also exacerbated it. Similar results were observed with the peroxisomal proliferator activated receptor gamma (PPARc) agonist rosiglitazone. Furthermore, hyperosmolality increased free intracellular arachidonic acid levels, which were even higher when prostaglandin synthesis was inhibited by indomethacin. Blocking PPARc with GW-9662 prevented the effects of both indomethacin and rosiglitazone on tri- glyceride synthesis and even reduced hyperosmolality-induced triglyceride syn- thesis, suggesting that arachidonic acid may stimulate triglyceride synthesis through PPARc activation. These results highlight the role of cPLA2 in osmo- protection, since it is essential to provide arachidonic acid, which is involved in PPARc-regulated triglyceride synthesis, thus guaranteeing cell survival.