Bone marrow-derived cPLA2α contributes to renal fibrosis progression

• Published in: Journal of lipid research 2018-02, Vol.59 (2), p.380-390
• Main Authors: Montford, John R., Lehman, Allison M.B., Bauer, Colin D., Klawitter, Jelena, Klawitter, Jost, Poczobutt, Joanna M., Scobey, Micah, Weiser-Evans, Mary, Nemenoff, Raphael A., Furgeson, Seth B.
• Format: Article
• Language: English
• Subjects: Actin; Animal models; Animals; Bone marrow; Bone Marrow - metabolism; Bone marrow transplantation; Calcium; CD11b antigen; CD45 antigen; Collagen; Cytokines; cytosolic calcium-dependent group IVA phospholipase A2α; Eicosanoids; extracellular matrix; Fibrosis; Fibrosis - metabolism; Fibrosis - pathology; Group IV Phospholipases A2 - deficiency; Group IV Phospholipases A2 - genetics; Group IV Phospholipases A2 - metabolism; Inflammation; kidney; Kidney Diseases - metabolism; Kidney Diseases - pathology; Kidneys; lipidomics; Macrophages; Mice; Mice, Inbred C57BL; Phospholipase A2; phospholipases/A2; Rodents; Smooth muscle; Ureteral Obstruction - metabolism; Ureteral Obstruction - pathology
• ISSN: 0022-2275; 1539-7262
• DOI: 10.1194/jlr.M082362

The group IVA calcium-dependent cytosolic phospholipase A2 (cPLA2α) enzyme directs a complex “eicosanoid storm” that accompanies the tissue response to injury. cPLA2α and its downstream eicosanoid mediators are also implicated in the pathogenesis of fibrosis in many organs, including the kidney. We aimed to determine the role of cPLA2α in bone marrow-derived cells in a murine model of renal fibrosis, unilateral ureteral obstruction (UUO). WT C57BL/6J mice were irradiated and engrafted with donor bone marrow from either WT mice [WT-bone marrow transplant (BMT)] or mice deficient in cPLA2α (KO-BMT). After full engraftment, mice underwent UUO and kidneys were collected 3, 7, and 14 days after injury. Using picrosirius red, collagen-3, and smooth muscle α actin staining, we determined that renal fibrosis was significantly attenuated in KO-BMT animals as compared with WT-BMT animals. Lipidomic analysis of homogenized kidneys demonstrated a time-dependent upregulation of pro-inflammatory eicosanoids after UUO; KO-BMT animals had lower levels of many of these eicosanoids. KO-BMT animals also had fewer infiltrating pro-inflammatory CD45+CD11b+Ly6Chi macrophages and reduced message levels of pro-inflammatory cytokines. Our results indicate that cPLA2α and/or its downstream mediators, produced by bone marrow-derived cells, play a major role in eicosanoid production after renal injury and in renal fibrinogenesis.