Prostaglandin E₂promotes cellular recovery from established nephrotoxic serum nephritis in mice, prosurvival, and regenerative effects on glomerular cells

Abstract

We postulated that prostaglandin E2 (PGE2), which exhibits regulatory functions to control immune-mediated inflammation, fibrosis, oxidative stress, and tissue/cellular regeneration, has the potential to improve the course of nephritis. Therefore, the therapeutic potential of prostanoid on established nephritis in mice was evaluated focusing on its role on renal cellular recovery, with emphasis on its cytoprotecting and growth-promoting effects. Acute nephritis was induced in mice by single injection of nephrotoxic serum (NTS), followed by PGE2 administration with severity of nephritis evaluated over time. Mice injected with PGE2 recovered promptly with normalization of blood urea nitrogen and urine protein levels and histology. Recovery was observed with dosing of prostanoid at day 1, as well as day 4. With the use of selective EP1-4 receptor agonists, EP3 receptor has been identified as important in mediating beneficial effects of PGE2 in our system. PGE2 normalized glomerular cell losses during nephrotoxic serum-induced nephritis, restored synaptopodin distribution and F-actin filaments arrangement in glomeruli. In cell culture, PGE2 reduced nephrotoxim serum (NTS)-induced apoptosis of glomerular cells and promoted cell reproliferation after NTS-mediated injury. In conclusion, PGE2 treatment promotes resolution of glomerular inflammation. Consistent with this observation, the regenerative and cytoprotective effects of prostanoid on glomerular cells in culture were observed, suggesting that PGE2 may be beneficial in the treatment of glomerulonephritis.

Activation of COX-2/mPGES-1/PGE2 Cascade via NLRP3 Inflammasome Contributes to Albumin-Induced Proximal Tubule Cell Injury

“…Among the inflammatory mediators, PGE2 has a known role in mediating the inflammatory response in various kidney injuries [11, 12, 33, 34]. Blockade of PGE2 production by inhibiting its synthetic enzymes of COX-2 or mPGES-1 could improve many kidney diseases in animals [19, 24, 35-37], suggesting a pathogenic role of COX-2/mPGES-1/ PGE2 pathway in kidney injury.…”

Prostaglandin E2 Inhibits NLRP3 Inflammasome Activation through EP4 Receptor and Intracellular Cyclic AMP in Human Macrophages

“…During the acute, initial stage of the inflammatory response PGE 2 acts as a vasodilator and facilitates tissue influx of neutrophils (20), macrophages (21) and mast cells (22) as well as a regulator of nociception (23). However, PGE 2 also has many potent immunosuppressive properties that contribute to the resolution phase of acute inflammation (24), facilitation of tissue regeneration (25) and the return to homeostasis (26). Yet in the context of many immunopathologies, those PGE 2 -mediated effects can lead to aggravation of the disease phenotype such as chronic inflammation or cancer (27).…”

PPARγAgonist Rosiglitazone Suppresses Renal mPGES-1/PGE2 Pathway in db/db Mice

“…Among five prostanoids of PGE2, PGD2, PGI2, PGF2 α , and thromboxane (TX) A2, PGI2 and TXA2 are important players in regulation of renal hemodynamics [5–7]; PGE2 serves as an important regulator of glomerular integrity, SS hemodynamics, and tubular fluid reabsorption [8–10], while the PGD2 and PGF2 α in kidney are less studied and their functions are poorly understood. …”