title: Albumin-induced podocyte injury and protection are associated with regulation of COX-2.
abstract: Albuminuria is both a hallmark and a risk factor for progressive glomerular disease, and results in increased exposure of podocytes to serum albumin with its associated factors. Here in vivo and in vitro models of serum albumin-overload were used to test the hypothesis that albumin-induced proteinuria and podocyte injury directly correlate with COX-2 induction. Albumin induced COX-2, MCP-1, CXCL1, and the stress protein HSP25 in both rat glomeruli and cultured podocytes, whereas B7-1 and HSP70i were also induced in podocytes. Podocyte exposure to albumin induced both mRNA and protein and enhanced the mRNA stability of COX-2, a key regulator of renal hemodynamics and inflammation, which renders podocytes susceptible to injury. Podocyte exposure to albumin also stimulated several kinases (p38 MAPK, MK2, JNK/SAPK, and ERK1/2), inhibitors of which (except JNK/SAPK) downregulated albumin-induced COX-2. Inhibition of AMPK, PKC, and NFκB also downregulated albumin-induced COX-2. Critically, albumin-induced COX-2 was also inhibited by glucocorticoids and thiazolidinediones, both of which directly protect podocytes against injury. Furthermore, specific albumin-associated fatty acids were identified as important contributors to COX-2 induction, podocyte injury, and proteinuria. Thus, COX-2 is associated with podocyte injury during albuminuria, as well as with the known podocyte protection imparted by glucocorticoids and thiazolidinediones. Moreover, COX-2 induction, podocyte damage, and albuminuria appear mediated largely by serum albumin-associated fatty acids.
authors.affiliation: Center for Clinical and Translational Research, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA.
authors.forename: Shipra
authors.initials: S
authors.lastname: Agrawal
authors.affiliation: Center for Clinical and Translational Research, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA.
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Guess
authors.affiliation: Center for Clinical and Translational Research, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA.
authors.forename: Melinda A
authors.initials: MA
authors.lastname: Chanley
authors.affiliation: 1] Center for Clinical and Translational Research, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA [2] Department of Pediatrics, The Ohio State University, Columbus, Ohio, USA.
authors.forename: William E
authors.initials: WE
authors.lastname: Smoyer
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors; D000419:Albuminuria / Q000201:enzymology*; D000818:Animals; D018122:B7-1 Antigen / Q000235:genetics; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics; D054360:Chemokine CXCL1 / Q000235:genetics; D051546:Cyclooxygenase 2 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D005227:Fatty Acids / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology; D055551:HSP27 Heat-Shock Proteins / Q000235:genetics; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics; D006360:Heat-Shock Proteins / Q000235:genetics; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D018832:Molecular Chaperones; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D009363:Neoplasm Proteins / Q000235:genetics; D050199:Podocytes / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D012710:Serum Albumin, Bovine / Q000494:pharmacology*; D045162:Thiazolidinediones / Q000494:pharmacology
chemical_list: D018122:B7-1 Antigen; C491768:Ccl2 protein, mouse; C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D054360:Chemokine CXCL1; C475895:Cxcl1 protein, mouse; C513297:Cxcl1 protein, rat; D005227:Fatty Acids; D005938:Glucocorticoids; D055551:HSP27 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; D006360:Heat-Shock Proteins; C486113:Hsbp1 protein, mouse; C486114:Hspb1 protein, rat; D018832:Molecular Chaperones; D016328:NF-kappa B; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D045162:Thiazolidinediones; D012710:Serum Albumin, Bovine; D051546:Cyclooxygenase 2; D011493:Protein Kinase C; D055372:AMP-Activated Protein Kinases