Tsukahara H, Krivenko Y, Moore L C, Goligorsky M S
Department of Medicine, Health Sciences Center, State University of New York, Stony Brook 11794-8152.
Am J Physiol. 1994 Jul;267(1 Pt 2):F190-5. doi: 10.1152/ajprenal.1994.267.1.F190.
It has been hypothesized that fluctuations of the ionic composition in the interstitium of juxtaglomerular apparatus (JGA) modulate the function of extraglomerular mesangial cells (MC), thereby participating in tubuloglomerular feedback (TGF) signal transmission. We examined the effects of isosmotic reductions in ambient sodium concentration ([Na+]) and [Cl-] on cytosolic calcium concentration ([Ca2+]i) in cultured rat MC. Rapid reduction of [Na+] or [Cl-] in the bath induced a concentration-dependent rise in [Ca2+]i. MC are much more sensitive to decreases in ambient [Cl-] than to [Na+]; a decrease in [Cl-] as small as 14 mM was sufficient to elicit a detectable [Ca2]i response. These observations suggest that MC can be readily stimulated by modest perturbations of extracellular [Cl-]. Next, we examined whether activation of MC by lowered ambient [Cl-] influences cellular nitric oxide (NO) production. Using an amperometric NO sensor, we found that a 13 mM decrease in ambient [Cl-] caused a rapid, Ca2+/calmodulin-dependent rise in NO release from MC. This response was not inhibitable by dexamethasone, indicating the involvement of the constitutive rather than the inducible type of NO synthase in MC. In addition, the NO release was blunted by indomethacin pretreatment, suggesting that a metabolite(s) of cyclooxygenase regulates the activation of NO synthase in MC. Our findings that small perturbations in external [Cl-] stimulate MC to release NO, a highly diffusible and rapidly acting vasodilator, provide a possible mechanism to explain the transmission of the signal for the TGF response within the JGA.
有假说认为，肾小球旁器（JGA）间质中离子成分的波动会调节球外系膜细胞（MC）的功能，从而参与管球反馈（TGF）信号传递。我们研究了等渗降低细胞外钠浓度（[Na+]）和[Cl-]对培养的大鼠MC胞质钙浓度（[Ca2+]i）的影响。浴液中[Na+]或[Cl-]的快速降低会引起[Ca2+]i浓度依赖性升高。MC对细胞外[Cl-]降低的敏感性远高于对[Na+]降低的敏感性；[Cl-]降低仅14 mM就足以引发可检测到的[Ca2+]i反应。这些观察结果表明，MC很容易受到细胞外[Cl-]适度扰动的刺激。接下来，我们研究了降低细胞外[Cl-]对MC的激活是否会影响细胞一氧化氮（NO）的产生。使用安培型NO传感器，我们发现细胞外[Cl-]降低13 mM会导致MC释放NO的量迅速、依赖Ca2+/钙调蛋白地增加。这种反应不受地塞米松抑制，表明MC中参与的是组成型而非诱导型NO合酶。此外，吲哚美辛预处理会使NO释放减弱，提示环氧化酶的一种代谢产物调节MC中NO合酶的激活。我们的研究结果表明，细胞外[Cl-]的微小扰动会刺激MC释放NO，NO是一种高度可扩散且作用迅速的血管舒张剂，这为解释JGA内TGF反应信号的传递提供了一种可能的机制。
