Restoration of Nephrotoxic Serum Induced Injury by PGE2 in Nephrotoxic Serum Nephritis in Mice and Glomerular Cells

Abstract

We postulated that PGE2, which exhibits multiple, tissue dependent regulatory functions to control immune‐mediated inflammation, tissue repair and fibrosis, has the potential to improve the course of ongoing nephritis. Therefore, the therapeutic potential and protective effect of exogenous PGE2 on established NTN in mice was evaluated along with its' cytoprotective effect on murine endothelial cells (GEC) and podocytes (POD). Initially, mice were injected with nephrotoxic serum (NTS), followed by PGE2 administration 5μg/g/d, started either on day 1, 2 or 3 after NTS dosing. Mice injected with PGE2 were protected, with normalization of BUN, Upr and histology. Protection was most beneficial with dosing at day 1, although later treatment was effective. Further, the capacity of PGE2 to limit injury of cultured cells was evaluated. Thus, POD and GEC were pretreated with PGE2, 1‐5μg/ml for 2–4h, and afterwards, NTS 5–10% was added for additional 7–12 h and apoptosis assessed by FACS. PGE2 reduced NTS induced apoptosis of cultured POD and GEC up to 30%. Furthermore, when POD and GEC were subjected to NTS, and then treated with PGE2 (1–5μg/ml), cell numbers were increased (25–55%) in a dose dependent fashion, indicating that PGE2 promoted cell regeneration after NTS induced injury. PGE2 also limited NTS induced GEC upregulation of CD47, an integrin associated protein; its' ligation in many cases leads to inhibition of cell proliferation and cell death. Altogether, the results indicate that PGE2 is candidate to further investigate its therapeutic potential to improve cellular recovery and improved function during the course of glomerulonephritis.The work was supported by NI‐HDDK 081140‐02.