Komers Radko, Schutzer William, Xue Hong, Oyama Terry T, Lindsley Jessie N, Anderson Sharon
Division of Nephrology and Hypertension, Oregon Health & Science University, Portland, Ore 97239, USA.
Transl Res. 2007 Dec;150(6):343-9. doi: 10.1016/j.trsl.2007.07.001. Epub 2007 Aug 15.
p38 mitogen-activated protein kinase (p38) has been implicated in mediating vascular smooth muscle and mesangial cell contraction in response to several vasoactive factors, including angiotensin II. Early stages of diabetic nephropathy are associated with renal hemodynamic changes that are, at least in part, attributable to the dysbalance of vasoactive factors that control afferent and efferent arteriolar tone resulting in increased glomerular capillary pressure. Vascular and renal p38 have been found to be activated in diabetes. Therefore, p38 may be involved in the control of systemic and renal hemodynamics in diabetes. To address this issue, mean arterial blood pressure (MAP), glomerular filtration rate (GFR, inulin clearance), renal plasma flow (RPF, PAH clearance), metabolic parameters, and plasma renin concentrations (PRC) were determined in streptozotocin-diabetic rats (DM), and in age-matched non-diabetic controls (C), administered with the p38 inhibitor SB 239063 (SB, 50 mg/bwt, p.o.) or with vehicle. Furthermore, renal vascular responses to p38 inhibition (SB 202190, 25 microM) before and after stimulation with the endothelium-dependent vasodilator acetylcholine (ACh) were studied in vitro in tertiary branches of the renal artery from separate groups of DM and C rats, using a fixed support and a force transducer in a myograph system. SB treatment was associated with marked reductions in MAP and GFR in both C and DM rats, whereas RPF remained unchanged, as compared with vehicle-treated animals. Observed differences in MAP and renal hemodynamics were not associated with changes in urinary sodium excretion or PRC. Incubation of KCl-contracted renal arteries from both C and DM rats with the p38 inhibitor resulted in progressive and significant vasorelaxation. Also, vessels from control and diabetic rats treated with the p38 inhibitor exhibited enhancement of ACh-induced vasorelaxation. These data indicate the role of p38 in the control of systemic and renal hemodynamics both in normal and in diabetic rats. The observed effects of p38 inhibition could be mediated at least in part by enhancement of endothelium-dependent vasodilation.
p38丝裂原活化蛋白激酶（p38）参与介导血管平滑肌和系膜细胞对包括血管紧张素II在内的多种血管活性因子的收缩反应。糖尿病肾病的早期阶段与肾血流动力学变化有关，这些变化至少部分归因于控制入球和出球小动脉张力的血管活性因子失衡，导致肾小球毛细血管压力升高。已发现糖尿病患者血管和肾脏中的p38被激活。因此，p38可能参与糖尿病患者全身和肾脏血流动力学的调控。为解决这一问题，我们测定了链脲佐菌素诱导的糖尿病大鼠（DM）和年龄匹配的非糖尿病对照大鼠（C）的平均动脉血压（MAP）、肾小球滤过率（GFR，菊粉清除率）、肾血浆流量（RPF，对氨基马尿酸清除率）、代谢参数和血浆肾素浓度（PRC），这些大鼠分别给予p38抑制剂SB 239063（SB，50 mg/kg体重，口服）或赋形剂。此外，在体外，使用肌动描记系统中的固定支架和力传感器，研究了来自不同组DM和C大鼠肾动脉三级分支在用内皮依赖性血管舒张剂乙酰胆碱（ACh）刺激前后对p38抑制（SB 202190，25 microM）的肾血管反应。与给予赋形剂的动物相比，SB处理使C组和DM组大鼠的MAP和GFR显著降低，而RPF保持不变。观察到的MAP和肾血流动力学差异与尿钠排泄或PRC的变化无关。用p38抑制剂孵育C组和DM组大鼠的氯化钾收缩肾动脉，导致血管逐渐且显著舒张。此外，用p38抑制剂处理的对照和糖尿病大鼠的血管对ACh诱导的血管舒张增强。这些数据表明p38在正常和糖尿病大鼠全身和肾脏血流动力学调控中的作用。观察到的p38抑制作用至少部分可能是通过增强内皮依赖性血管舒张介导的。
