Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia Health System, Charlottesville, VA 22908-1414, USA.
Hypertension. 2011 Jul;58(1):107-13. doi: 10.1161/HYPERTENSIONAHA.110.168708. Epub 2011 Apr 11.
cGMP functions as an extracellular (paracrine) messenger acting at the renal proximal tubule and is an important modulator of pressure-natriuresis (P-N). The signaling pathway activated by cGMP in the tubule cell basolateral membrane remains unknown. We hypothesized that renal interstitial microinfusion of cGMP (50 nmol/kg per minute) or P-N would be accompanied by increased renal protein levels of phospho-Src (Tyr 416) and that the natriuresis would be decreased by Src inhibition. Renal interstitial cGMP-induced natriuresis was blocked by Src inhibitor PP2 (2.0±0.4 versus 0.5±0.01 μEq/g per minute; P<0.001). The inactive analog of PP2, PP3, had no effect on cGMP-induced natriuresis. SU6656, another Src inhibitor, also inhibited cGMP-induced natriuresis (2.0±0.4 versus 1.02±0.01 μEq/g per minute; P<0.001). Renal interstitial cGMP infusion increased phospho-Src protein levels 5.6-fold at 15 minutes and 6.8-fold at 30 minutes compared with vehicle infusion but returned toward basal levels after 60 minutes. PP2 also blunted P-N (3.1±0.1 versus 1.1±0.3 μEq/g per minute; P<0.01) despite a similar increase in blood pressure. PP3 had no effect on P-N. Phospho-Src protein levels increased during P-N in vehicle- (1.8-fold) and PP3-treated (2.1-fold) groups compared with the sham-operated group. PP2 blocked the pressure-induced increase in renal phospho-Src protein levels. PP2 had no effect on renal hemodynamics but decreased both fractional excretion of Na(+) and lithium. Both extracellular cGMP and increased renal perfusion pressure increased renal phospho-Src protein levels and induced natriuresis in an Src-dependent manner, demonstrating that Src is an important downstream signaling molecule for extracellular cGMP-induced natriuresis.
cGMP 作为一种细胞外（旁分泌）信使，作用于肾脏近端小管，是压力-利钠作用（P-N）的重要调节剂。cGMP 在肾小管细胞基底外侧膜中激活的信号通路尚不清楚。我们假设，肾间质中 cGMP（50nmol/kg/min）或 P-N 的微输注将伴随着肾蛋白磷酸化Src（Tyr416）水平的增加，而 Src 抑制将减少利钠作用。肾间质 cGMP 诱导的利钠作用被 Src 抑制剂 PP2 阻断（2.0±0.4 与 0.5±0.01μEq/g/min；P<0.001）。PP2 的无活性类似物 PP3 对 cGMP 诱导的利钠作用没有影响。另一种 Src 抑制剂 SU6656 也抑制了 cGMP 诱导的利钠作用（2.0±0.4 与 1.02±0.01μEq/g/min；P<0.001）。肾间质 cGMP 输注在 15 分钟时使磷酸化 Src 蛋白水平增加 5.6 倍，在 30 分钟时增加 6.8 倍，与载体输注相比，但在 60 分钟后恢复到基础水平。PP2 也使 P-N 减弱（3.1±0.1 与 1.1±0.3μEq/g/min；P<0.01），尽管血压有类似的升高。PP3 对 P-N 没有影响。在载体（1.8 倍）和 PP3 处理（2.1 倍）组中，磷酸化 Src 蛋白水平在 P-N 期间增加，与假手术组相比。PP2 阻断了压力诱导的肾磷酸化 Src 蛋白水平增加。PP2 对肾血流动力学没有影响，但降低了钠（Na+）和锂的分数排泄。细胞外 cGMP 和增加的肾灌注压均以 Src 依赖的方式增加肾磷酸化 Src 蛋白水平并诱导利钠作用，表明 Src 是细胞外 cGMP 诱导利钠作用的重要下游信号分子。
