title: Inhibition of p38 mitogen-activated protein kinase is effective in the treatment of experimental crescentic glomerulonephritis and suppresses monocyte chemoattractant protein-1 but not IL-1beta or IL-6.
abstract: Activation of p38 mitogen-activated protein kinase (MAPK) is known to be important in cytokine production and cell survival in inflammation. This study examined the effect of inhibiting p38 MAPK after onset of renal injury in an experimental model of crescentic glomerulonephritis. Furthermore, this study investigated whether p38 MAPK inhibition would cause widespread suppression of the cytokine network in vivo or uncontrolled apoptosis. In the in vivo studies, daily treatment with a p38 MAPKalpha/beta inhibitor was started 1 h (early treatment study) or 4 d (late treatment study) after induction of nephrotoxic nephritis in Wistar Kyoto rats. The treated rats remained healthy with normal weight gain during the study. Both early and late treatment with p38 MAPK inhibitor reduced renal monocyte chemoattractant protein-1 (MCP-1) levels, the number of glomerular macrophages, the severity of tissue injury, and proteinuria compared with the vehicle group. Unexpected, treatment with p38 MAPK inhibitor did not suppress renal levels of IL-1beta or IL-6. In the in vitro study, the p38 MAPKalpha/beta inhibitor reduced production of MCP-1 and IL-6 by TNF-alpha-or IL-1beta-stimulated mesangial cells without any effect on cell viability or apoptosis. In conclusion, p38 MAPK inhibition is effective in reducing the severity of crescentic glomerulonephritis even when treatment is started after onset of disease. The therapeutic effect is associated with selective suppression of MCP-1, without widespread suppression of cytokine production or increased apoptosis. Therefore, p38 MAPK therapeutic blockade is a promising strategy in the treatment of antibody-mediated glomerulonephritis.
authors.affiliation: Renal Section, Division of Medicine, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 ONN, UK.
authors.forename: Abdulmunem
authors.initials: A
authors.lastname: Sheryanna
authors.forename: Gurjeet
authors.initials: G
authors.lastname: Bhangal
authors.forename: John
authors.initials: J
authors.lastname: McDaid
authors.forename: Jennifer
authors.initials: J
authors.lastname: Smith
authors.forename: Anthony
authors.initials: A
authors.lastname: Manning
authors.forename: Brian M J
authors.initials: BM
authors.lastname: Foxwell
authors.forename: Marc
authors.initials: M
authors.lastname: Feldmann
authors.forename: H Terence
authors.initials: HT
authors.lastname: Cook
authors.forename: Charles D
authors.initials: CD
authors.lastname: Pusey
authors.forename: Frederick W K
authors.initials: FW
authors.lastname: Tam
mesh_terms: D000818:Animals; D018932:Chemokine CCL2 / Q000032:analysis / Q000037:antagonists & inhibitors*; D005921:Glomerulonephritis / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis; D053583:Interleukin-1beta / Q000032:analysis / Q000037:antagonists & inhibitors*; D015850:Interleukin-6 / Q000032:analysis; D008297:Male; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D051381:Rats; D011921:Rats, Inbred WKY; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D000093242:Interleukin-6 Inhibitors
chemical_list: D018932:Chemokine CCL2; D018799:Intercellular Adhesion Molecule-1; D053583:Interleukin-1beta; D015850:Interleukin-6; D047428:Protein Kinase Inhibitors; D048051:p38 Mitogen-Activated Protein Kinases; D000093242:Interleukin-6 Inhibitors