title: 14S,21R-dihydroxy-docosahexaenoic acid treatment enhances mesenchymal stem cell amelioration of renal ischemia/reperfusion injury.
abstract: Bone marrow mesenchymal stem cells (MSCs) have shown potential to improve treatment of renal failure. The prohealing functions of MSCs have been found to be enhanced by treatment with the lipid mediator, 14S,21R-dihydroxy-docosa4Z,7Z,10Z,12E,16Z,19Z-hexaenoic acid (14S,21R-diHDHA). In this article, using a murine model of renal ischemia/reperfusion (I/R) injury, we found that treatment with 14S,21R-diHDHA enhanced MSC amelioration of renal I/R injury. Treated MSCs more efficiently inhibited I/R-induced elevation of serum creatinine levels, reduced renal tubular cell death, and inhibited infiltration of neutrophils, macrophages, and dendritic cells in kidneys. Conditioned medium from treated MSCs reduced the generation of tumor necrosis factor-α and reactive oxygen species by macrophages under I/R conditions. Infusion of treated MSCs more efficiently reduced I/R-damage to renal histological structures compared with untreated MSCs (injury score: 7.9±0.4 vs. 10.5±0.5). Treated MSCs were resistant to apoptosis in vivo when transplanted under capsules of I/R-injured kidneys (active caspase-3+ MSCs: 4.2%±2.8% vs. 11.7%±2.4% of control) and in vitro when cultured under I/R conditions. Treatment with 14S,21R-diHDHA promoted viability of MSCs through a mechanism involving activation of the phosphoinositide 3-kinase -Akt signaling pathway. Additionally, treatment of MSCs with 14S,21R-diHDHA promoted secretion of renotrophic hepatocyte growth factor and insulin growth factor-1. Similar results were obtained when 14S,21RdiHDHA was used to inhibit apoptosis of human MSCs (hMSCs) and to increase the generation of renotrophic cytokines from hMSCs. These findings provide a lead for new strategies in the treatment of acute kidney injury with MSCs.
authors.affiliation: Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
authors.forename: Haibin
authors.initials: H
authors.lastname: Tian
authors.forename: Yan
authors.initials: Y
authors.lastname: Lu
authors.forename: Shraddha P
authors.initials: SP
authors.lastname: Shah
authors.forename: Quansheng
authors.initials: Q
authors.lastname: Wang
authors.forename: Song
authors.initials: S
authors.lastname: Hong
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003404:Creatinine / Q000097:blood; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D005260:Female; D017228:Hepatocyte Growth Factor / Q000096:biosynthesis / Q000378:metabolism; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000096:biosynthesis / Q000378:metabolism; D007511:Ischemia / Q000628:therapy*; D007668:Kidney / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000502:physiology; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D017382:Reactive Oxygen Species / Q000378:metabolism; D015427:Reperfusion Injury / Q000097:blood / Q000628:therapy*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: C569432:14,21-dihydroxydocosa-4,7,10,12,16,19-hexaenoic acid; D000893:Anti-Inflammatory Agents; D018836:Inflammation Mediators; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D004281:Docosahexaenoic Acids; D017228:Hepatocyte Growth Factor; D007334:Insulin-Like Growth Factor I; D003404:Creatinine