Hemodynamic role of arachidonate 12- and 5-lipoxygenases in nephrotoxic serum nephritis

Abstract

The role of arachidonate 12- and 5-lipoxygenation eicosanoids in mediating acute changes in renal hemodynamics was assessed in nephrotoxic serum nephritis (NSN) in the rat. Following a single intravenous injection of nephrotoxic serum (NTS), significant decrements in glomerular filtration rate (GFR) and renal blood flow (RBF) occurred at one hour, and were associated with increments in glomerular polymorphonuclear leukocyte (PMN) counts and in the synthesis of thromboxane (Tx) B2, leukotriene (LT) B4 and 12-hydroxyeicosatetraenoic acid (12-HETE). Pretreatment of rats with the arachidonate 12-lipoxygenase inhibitor, baicalein, partially but significantly ameliorated the decrements in GFR and RBF, and blocked the enhanced glomerular synthesis of 12-HETE following administration of NTS. Likewise, pretreatment of rats with the arachidonate 5-lipoxygenase inhibitor, U-66858, partially ameliorated the decrements in GFR and RBF induced by NTS. Combined pretreatment of rats with baicalein and U-66858 ameliorated the decrements in GFR and RBF to an extent no different to that of U-66858 alone. In rats pretreated with the LTB4 receptor antagonist, U-75302, GFR and RBF remained depressed to levels no different than in animals which received NTS alone. These observations indicate that in NSN, the acute decrements in GFR and RBF are partially mediated by 12-HETE and arachidonate 5-lipoxygenation products. Leukotrienes other than LTB4, such as LTD4 and LTC4, are the likely candidates.