PGE₂-mediated cytoprotection in renal epithelial cells: evidence for a pharmacologically distinct receptor

Abstract

Although the exact mechanism of prostaglandin E2(PGE2)-mediated cytoprotection has not been elucidated, its ability to induce cytoprotection in cell culture suggests this action occurs at the cellular level. The present studies were conducted to determine whether PGE2 induces protection against 2,3,5-(trisglutathion- S-yl)-hydroquinone [2,3,5-(trisglutathion- S-yl)-HQ]-mediated cytotoxicity in a renal proximal tubule epithelial cell line (LLC-PK1) and to delineate the cellular and molecular mechanisms associated with this response. Pretreatment of LLC-PK1 cells with 0.01–40 μM PGE2 for 24 h fully protects against a moderately toxic concentration of 2,3,5-(trisglutathion- S-yl)-HQ. PGE2-mediated cytoprotection is observed in cells pretreated at pH 7.4 but not at pH 7.8. However, cytoprotection is observed in LLC-PK1 cells pretreated with the PGE2 analog, 11-deoxy-16,16-dimethyl PGE2(DDM-PGE2) but not with the PGE2 receptor [E-prostanoid (EP)] agonists 17-phenyltrinor PGE2(EP1), 11-deoxy PGE1(EP2/EP4), sulprostone (EP1/EP3), PGE1, or PGA2. 12- O-tetradecanoylphorbol-13-acetate (TPA), a potent activator of protein kinase C (PKC), also induces cytoprotection, supporting a role for this pathway in the cytoprotective response. PGE2, DDM-PGE2, and TPA all induce the binding of nuclear proteins to a TPA responsive element (TRE), whereas analogs that did not induce cytoprotection (PGE1, 17-phenyltrinor PGE2, sulprostone) were without effect. DDM-PGE2- and TPA-mediated cytoprotection and TRE binding activity are inhibited by N-(2{[3-(4-bromophenyl)-2-propenyl]-amino}-ethyl)-5-isoquinolinesulfonamide (H-89), a PKC inhibitor. These data suggest that cytoprotection by PGE2 and DDM-PGE2 in LLC-PK1 cells is mediated by a PKC-coupled receptor, which is pharmacologically distinct from the presently classified EP receptor subtypes.

Distinct Roles for Basal and Induced COX-2 in Podocyte Injury

“…Recently, PGE 2 was reported to initiate a positive feedback loop via EP 4 in the podocyte signaling network, activated by increased glomerular capillary pressure, which could be detrimental to podocyte health and glomerular filtration barrier integrity. 17 However, other studies have suggested that PGE 2 serves a cytoprotective function in renal epithelial cells 18,19 In other cell types, PGE 2 has been shown to promote cell survival, cell growth, migration, invasion, and angiogenesis. 20,21 In this regard, podocytes from COX-2-knockout mice were found to exhibit significant apoptosis even under basal conditions, suggesting that COX-2-derived prostaglandins also may serve a trophic cytoprotective function.…”

Short-Term Regulation of Basolateral Organic Anion Uptake in Proximal Tubular Opossum Kidney Cells

“…In addition, reasonable amounts of the EP2 selective agonist butaprost (Km approximately 100 nM; (40)) do not affect basolateral organic uptake rate, neither after 10 min nor acutely. The EP selective agonists used were shown to act not only in rodents but also in cells from pigs (41) and humans (15). Thus, their pharmacologic profile seems not to be strictly species dependent.…”

Protection against proximal tubule necrosis with 11-deoxy-16,16-dimethyl prostaglandin E2 in vitro

“…They have sequentially characterized the signaling pathways of renal proximal tubule (LLC-PK 1 cells) protection with DDM-PGE 2 in previous studies. They showed that DDM-PGE 2 protects against necrosis via thromboxane receptor activation through a PKC signal transduction pathway coupled to NF-B (20). They also showed the upregulation of several potential cytoprotective proteins, including glucose-regulated protein 78 (Grp78).…”