Regulatory interactions between inducible nitric oxide synthase and eicosanoids in glomerular immune injury

Abstract

In a rat model of glomerular immune injury induced by administration of anti-glomerular basement membrane antibody and resembling human rapidly progressive glomerulonephritis, we explored whether activation of inducible nitric oxide synthase (iNOS) regulates synthesis of eicosanoids originating from cyclooxygenation or lipoxygenation of arachidonic acid. At early stages (24 hr) of injury, inhibition of iNOS using the selective inhibitor L-N6-(1-iminoethyl) lysine (L-NIL) at doses sufficient to reduce urinary excretion of nitrate/nitrite, reduced glomerular synthesis of the prostaglandins PGE2 and PGI2, but had no effect on that of thromboxane A2 (TxA2). The syntheses of 5-hydroxyeicosatetraenoic acid (HETE), 15-HETE and leukotriene B4 (LTB4) were also reduced. That of 12-HETE remained unchanged. We also explored the effect of arachidonate cyclooxygenation and lipoxygenation eicosanoids on iNOS expression. Administration of the cyclooxygenase (COX) inhibitor, indomethacin, at doses sufficient to inhibit glomerular prostaglandin synthesis, increased iNOS mRNA levels in glomeruli. Administration of the 5-lipoxygenase (5-LO) inhibitor, MK-0591, at doses sufficient to inhibit glomerular LTB4 synthesis also increased iNOS mRNA. The effect of 5-LO inhibition on iNOS expression was more pronounced than that of COX inhibition. In nephritic animals given the iNOS inhibitor, L-NIL, or indomethacin proteinuria worsened. In those given the 5-lipoxygenase inhibitor there was no change in urine protein excretion. These observations point to regulatory interactions between the arachidonic acid and the L-arginine: NO pathways in glomerulonephritis. These interactions are of importance in considering antiinflammatory strategies based on inhibition of iNOS or of specific eicosanoids.

PPAR Agonists Amplify iNOS Expression While Inhibiting NF-κB

“…As an alternative mechanism, activation of PPAR could enhance cytokine-elicited iNOS induction by promoting the degradation of lipidic negative modulators, among which could be some COX products, including PG of the J series, like 15d-PGJ 2 . In fact, inhibition of COX activity has been reported to lead to enhanced iNOS expression in a model of immune glomerulonephritis (49). At this point, however, our results do not support the involvement of PPAR in the effects herein described.…”

Nitric oxide preserves the glomerular protein permeability barrier by antagonizing superoxide

“…Neuronal NOS (nNOS) is primarily found at the macula densa where it is a physiologic component of the tubuloglomerular feedback loop and regulates the tone of afferent arteriole via production of nitric oxide [24]. The inducible NOS isoform (iNOS) is not expressed in normal rat glomeruli [4,25] which primarily express the constitutive NOS isoforms are more abundant than that of iNOS [26,27]. Normal rat glomeruli and cultured glomerular cells also produce O 2 − at baseline and in response to inflammatory mediators [1][2][3]28].…”

Role of Nitric Oxide in Inflammatory Conditions

“…NO has been identified in models of immune renal injury [13, 14, 15]. Furusu et al [16]have shown that the immunohistochemical localization of iNOS in human glomerulonephritis increases during disease, whereas eNOS staining decreases as compared with biopsy specimens from healthy individuals.…”

“…N G -nitro- L -arginine methyl ester treatment reduced macrophage infiltration and resulted in significant increases in eNOS [13]. Lianos et al [15]have reported worsening of proteinuria in glomerulonephritic rats treated with the specific iNOS inhibitor L -N 6 -(1-iminoethyl)lysine ( L -NIL).…”