Prostaglandin E_2 promotes cellular recovery from established nephrotoxic serum nephritis in mice, prosurvival, and regenerative effects on glomerular cells

摘要

We postulated that prostaglandin E_2 (PGE_2), 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 PGE_2 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, PGE_2 reduced nephrotoxim serum (NTS)-induced apoptosis of glomerular cells and promoted cell reproliferation after NTS-mediated injury. In conclusion, PGE_22 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 PGE_2 may be beneficial in the treatment of glomerulonephritis.