Waddington S N, Tam F W, Cook H T, Cattell V
Department of Histopathology, Imperial College School of Medicine at St. Mary's, London, United Kingdom.
Am J Physiol. 1998 Mar;274(3):F473-80. doi: 10.1152/ajprenal.1998.274.3.F473.
Arginase shares a common substrate, L-arginine, with nitric oxide synthase (NOS). Both enzymes are active at inflammatory sites. To understand regulation of arginase and its relationship to nitric oxide (NO) production, we studied effects of NG-hydroxy-L-arginine (HOArg) and interleukin-4 (IL-4) on urea and NO2- synthesis by glomeruli during rat immune glomerulonephritis and compared these with macrophages and glomerular mesangial cells (MC). In nephritic glomeruli, elicited macrophages, and MC stimulated with IL-1 and adenosine 3',5'-cyclic monophosphate agonists, increased arginase and induced NOS activity was found. Urea production was inhibited by HOArg and increased by IL-4. NO inhibition [NG-monomethyl-L-arginine (L-NMMA)] increased arginase activity in nephritic glomeruli and macrophages but not MC. NO2- synthesis was inhibited by L-NMMA and IL-4. It was increased with HOArg under conditions of NO inhibition. In contrast, in normal glomeruli and basal MC, where there was no induced NO synthesis, IL-4 had no effect on arginase activity, whereas HOArg consistently reduced it in glomeruli only. Type II arginase (Arg II) mRNA was detected in normal glomeruli; nephritic glomeruli expressed both Arg I and Arg II mRNAs. This is the first demonstration of arginase modulation in glomeruli and MC and of the expression of arginase isoforms in glomeruli. The differential responses to two endogenous compounds generated by inflammation suggest this may be part of coordinated regulation of arginase and inducible NOS in immune injury, whereby arginase is inhibited during high-output NO production and stimulated with NO suppression. This, together with control of arginase and NOS isoforms, may be important in controlling the balance of inflammatory and repair mechanisms.
精氨酸酶与一氧化氮合酶（NOS）共用一种共同底物L-精氨酸。这两种酶在炎症部位均具有活性。为了解精氨酸酶的调节及其与一氧化氮（NO）生成的关系，我们研究了NG-羟基-L-精氨酸（HOArg）和白细胞介素-4（IL-4）对大鼠免疫性肾小球肾炎期间肾小球尿素和NO₂⁻合成的影响，并将其与巨噬细胞和肾小球系膜细胞（MC）进行比较。在肾炎性肾小球、诱发的巨噬细胞以及用白细胞介素-1和腺苷3',5'-环磷酸激动剂刺激的MC中，发现精氨酸酶增加且诱导型NOS活性增强。HOArg可抑制尿素生成，而IL-4可使其增加。NO抑制剂[NG-单甲基-L-精氨酸（L-NMMA）]可增加肾炎性肾小球和巨噬细胞中的精氨酸酶活性，但对MC无此作用。L-NMMA和IL-4可抑制NO₂⁻合成。在NO抑制条件下，HOArg可使其增加。相反，在正常肾小球和基础MC中，未诱导出NO合成，IL-4对精氨酸酶活性无影响，而HOArg仅持续降低肾小球中的精氨酸酶活性。在正常肾小球中检测到II型精氨酸酶（Arg II）mRNA；肾炎性肾小球同时表达Arg I和Arg II mRNA。这是首次证明肾小球和MC中精氨酸酶的调节以及肾小球中精氨酸酶同工型的表达。对炎症产生的两种内源性化合物的不同反应表明，这可能是免疫损伤中精氨酸酶和诱导型NOS协调调节的一部分，即高产量NO生成期间精氨酸酶受到抑制，而NO受抑制时精氨酸酶受到刺激。这与精氨酸酶和NOS同工型的控制一起可能对控制炎症和修复机制的平衡很重要。
