一氧化氮在腎臟發炎反應中扮演重要角色，過量之一氧化氮生成會破壞腎臟機能，並促使腎小球腎炎之發生。許多的研究藉由調控誘發型一氧化氮合成脢來降低一氧化氮過量所造成之細胞毒害。大多數的研究報告都集中重點在轉錄層次上來調控誘發型一氧化氮合成脢；只有少數論文提及誘發型一氧化氮合成脢可在後轉譯層次上受到調控。我們的結果顯示，前列腺素E2抗拮劑(AH23848)可藉由減弱細胞內環腺甘酸含量及加速誘發型一氧化氮合成脢蛋白的分解，來抑制腎絲球細胞中產生的一氧化氮。前列腺素E2抗拮劑加速誘發型一氧化氮合成脢蛋白分解是透過蛋白質激脢A，因為蛋白質激脢A的抑制劑亦可加速誘發型一氧化氮合成脢蛋白的分解。由於實驗結果亦顯示誘發型一氧化氮合成脢可被絲氨基酸╱滋利氨基酸蛋白質激脢磷酸化，並且影響誘發型一氧化氮合成脢之活性。我們推測誘發型一氧化氮合成脢在後轉譯層次上所受到之調控與其蛋白質穩定度有關。
Excessive release of nitric oxide (NO) by mesangial cells contributes to the pathogenesis of glomerulonephritis. Prostaglandin E2 (PGE2) produced at inflammatory sites regulates the release of NO through its downstream signaling. In glomerular mesangial cells (MES-13 cells), PGE2 modulated NO production mainly through EP4 receptor in a cAMP-dependent manner. Lipopolysaccharide and interferon-gamma (LPS + IFNgamma)-induced NO production, inducible nitric oxide synthase (iNOS) gene and protein expression were greatly inhibited by AH23848, an EP4 antagonist. Further investigation indicated that AH23848 attenuated endogenous cAMP accumulation in MES-13 cells and modulated NO production through declination of iNOS gene expression and acceleration of iNOS protein degradation. AH23848 downregulated the iNOS protein in MES-13 cells through protein kinase A (PKA) since KT5720, a PKA-specific inhibitor, reduced iNOS protein stability. A short exposure of activated MES-13 cells to okadaic acid augmented iNOS activity. The results of this study led us to speculate that cAMP might regulate iNOS-stimulated NO synthesis through posttranslational mechanisms. Attenuation of cAMP signaling and the phosphorylation status of the iNOS protein may account for the effect of AH23848 in accelerating iNOS protein degradation in MES-13 cells.
