We assessed the effect of a cytokine inhibitor, compound SKF 86002 (a bicyclic imidazole), on changes in renal hemodynamics (renal blood flow and glomerular filtration rate) that occur acutely following immune injury of glomerular mesangial cells.
Methods
Injury was induced in Munich-Wistar rats by the administration of a monoclonal antibody against the mesangial cell membrane antigen Thy 1.1. An acute drop in renal blood flow (RBF) and glomerular filtration rate (GFR) occurred within one hour of injury.
Results
Pretreatment of animals with the cytokine inhibitor SKF 86002 prevented this drop. SKF 86002 had no effect on glomerular synthesis of vasoconstrictor eicosanoids.
Conclusions
The observations indicate that in mesangial cell immune injury, cytokines mediate renal hemodynamic impairment.
BresnahanBA, WuS, FenoyFJ, RomanRJ, LianosEA. Mesangial cell immune injury: hemodynamic role of leukocyte and platelet-derived eicosanoids. J Clin Invest1992;90:2304–12.
2.
LianosEA, BresnahanBA, PanCG. Mesangial cell immune injury. Synthesis, origin and role of eicosanoids. J Clin Invest1991:88:623–31.
3.
IidaH, SeifertR, AlpersCE, GronwaldRGK, PhillipsPE, PritzlP, GordonK, GownAM, RossR, Bowen-PopeDF, JohnsonRJ. Platelet-derived growth factor (PDGF) and PDGF receptor are induced in mesangial proliferative nephritis in the rat. Proc Natl Acad Sci USA1991;88:6560–4.
4.
YoshimuraA, GordonK, AlpersCE, FloegeJ, PritzlP, RossR, CouserW, Bowen-PopeDF, JohnsonRJ. Demonstration of PDGF β-chain mRNA in glomeruli in mesangial proliferative nephritis by in situ hybridization. Kidney Int1991;40:470–6.
5.
OkudaS, LanguinoLR, RuoslahtiE, BorderWA. Elevated expression of transforming growth factor-β and proteoglycan production in experimental glomerulonephritis. J Clin Invest1990;86:453–62.
BourgeoisN, ReuseC, BoeynaemsJM, StaroukineM, VanheweghemJL. Effects of endotoxin on hemodynamics of isolated dog kidney. Adv Exp Med Biol1987;212:81–5.
10.
BertaniT, AbbateM, ZojaC, CornaD, PericoN, GhezziP, RemuzziG.Tumor necrosis induces glomerular damage in the rabbit. Am J Path1989;134:419–30.
11.
LeeJC, BadgerAM, GriswoldDE, DunningtonD, TrunehA, VottaB, WhiteJR, YoungPR, BenderPE. Bicyclic imidazoles as a novel class of cytokine biosynthesis inhibitors. Ann NY Acad Sci1993;696:149–70.
12.
YoungP, McDonnelP, DunningtonD, HandA, LaydonJ, LeeJ.Pyridinyl imidazoles inhibit IL-1 and TNF- production at the protein level. Agents Actions1993;39:C67–9.
13.
GriswoldDE, MarshallPJ, WebbEF, GodfreyR, NewtonJ, DiMartinoMJ, SarauHM, GleasonJ, PosteG, HannaN.SK…F 86002: a structurally novel anti-inflammatory agent that inhibits lipoxygenase- and cyclooxygenase-mediated metabolism of arachidonic acid. Biochem Pharmacol1987;36:3463–70.
14.
FloegeJ, EngE, YoungBA, JohnsonRJ. Factors involved in the regulation of mesangial cell proliferation in vitro and in vivo. Kidney Int1993;43:S47–54.
15.
KlahrS, SchreinerG, IchikawaI.The progression of renal disease. N Engl J Med1988;18:1657–66.
16.
KonV, YoshiokaT, FogoA, IchikawaI.Glomerular actions of endothelin in vivo. J Clin Invest1989;83:1762–7.
17.
KohanD.Production of endothelin-1 by mesangial cells: regulation by tumor necrosis factor. J Lab Clin Med1992;119:477–84.
18.
MatthewN.Tumor necrosis factor from the rabbit. V. Synthesis in vitro by mononuclear phagocytes from various tissues of normal and BCG-injected rabbits. Br J Cancer1981;44:418.
