Poole Brian, Wang Wei, Chen Yung-Chang, Zolty Einath, Falk Sandor, Mitra Amitabha, Schrier Robert
Department of Medicine, University of Colorado Health Sciences Center, Denver, 80262, USA.
Am J Physiol Renal Physiol. 2005 Dec;289(6):F1382-5. doi: 10.1152/ajprenal.00402.2004. Epub 2005 Jul 26.
The pathogenesis of septic acute renal failure (ARF) involves systemic vasodilation with compensatory upregulation of vasoconstrictors. This can lead to renal vasoconstriction and ARF. Heme oxygenase (HO) is the rate-limiting step in heme metabolism and produces carbon monoxide (CO) and biliverdin. HO-1 is an inducible form of the enzyme and is expressed in response to cell injury. It was hypothesized in endotoxemia, induction of HO-1 would lead to increased production of the vasodilator CO, lower blood pressure, and decrease renal function. The role of HO-1 was therefore examined in a mouse model of endotoxemia. One group of mice received LPS alone and were compared with mice that received LPS in addition to an inhibitor of HO-1, zinc protoporphyrin (ZnPP). Treatment of mice with LPS resulted in significant increases in the protein expression of HO-1 compared with controls treated with vehicle. Immunohistochemical analysis localized this upregulation to both the proximal and distal tubules as well as the vasculature. Hemodynamic studies were performed during endotoxemia and the mean arterial pressure (MAP) was found to be significantly higher in the HO-1 inhibitor-treated compared with vehicle-treated mice (78 +/- 3 vs. 64 +/- 2 mmHg, P < 0.01). It was found that the inhibitor group had higher renal blood flows (RBF) also during endotoxemia (1.8 +/- 0.2 vs. 0.68 +/- 0.1 ml/min, P < 0.01). Furthermore, when renal vascular resistance (RVR) was calculated, there was a significant decrease in RVR in the inhibitor group (43.5 +/- 3.4 vs. 95.9 +/- 11.3 mmHg.ml(-1).min(-1), P < 0.01). In concert with the hemodynamic data, glomerular filtration rate (GFR), as measured by inulin clearance, was higher in the HO inhibitor compared with the vehicle controls during endotoxemia (111.5 +/- 19.5 vs. 66.0 +/- 3.5 microl/min, P < 0.05). In summary, during endotoxemia ARF, inhibiting HO-1 with ZnPP resulted in the protection of renal function. The renal protection was associated with significantly improved systemic hemodynamics, less renal vasoconstriction, and a higher GFR.
脓毒症急性肾衰竭（ARF）的发病机制涉及全身血管舒张以及血管收缩剂的代偿性上调。这会导致肾血管收缩和ARF。血红素加氧酶（HO）是血红素代谢的限速步骤，可产生一氧化碳（CO）和胆绿素。HO-1是该酶的诱导型，在细胞损伤时表达。在内毒素血症中曾有假说认为，HO-1的诱导会导致血管舒张剂CO的产生增加、血压降低以及肾功能下降。因此，在内毒素血症小鼠模型中研究了HO-1的作用。一组小鼠仅接受脂多糖（LPS），并与除接受LPS外还接受HO-1抑制剂锌原卟啉（ZnPP）的小鼠进行比较。与用赋形剂处理的对照相比，用LPS处理小鼠导致HO-1的蛋白表达显著增加。免疫组织化学分析将这种上调定位于近端和远端小管以及脉管系统。在内毒素血症期间进行了血流动力学研究，发现与用赋形剂处理的小鼠相比，用HO-1抑制剂处理的小鼠平均动脉压（MAP）显著更高（78±3 vs. 64±2 mmHg，P<0.01）。还发现抑制剂组在内毒素血症期间也有更高的肾血流量（RBF）（1.8±0.2 vs. 0.68±0.1 ml/min，P<0.01）。此外，计算肾血管阻力（RVR）时，抑制剂组的RVR显著降低（43.5±3.4 vs. 95.9±11.3 mmHg.ml-1.min-1，P<0.01）。与血流动力学数据一致，在内毒素血症期间，用菊粉清除率测量的肾小球滤过率（GFR）在HO抑制剂组中高于赋形剂对照组（111.5±19.5 vs. 66.0±3.5 μl/min，P<0.05）。总之，在内毒素血症性ARF期间，用ZnPP抑制HO-1可保护肾功能。肾脏保护与全身血流动力学显著改善、肾血管收缩减轻以及更高的GFR相关。
