Elucidation of Tubulo-Glomerular Feedback Mechanisms

推测肾小管-肾小球反馈(TGF)活性异常可能通过肾血流动力学改变导致肾病。然而，目前还没有一种实用的技术来评估转化生长因子的活性。本项目的目的是建立体内动态方法来评价转化生长因子的活性，评价肾脏疾病模型中转化生长因子的活性，并确定转化生长因子的可能机制。1.体内动态评价转化生长因子活性的方法的发展：我们引入了活体内可直接观察肾脏微循环的CCD-视频显微镜，并测量了大鼠肾小动脉的传入和传出直径。SD大鼠的基础传入动脉直径为8.57±0.43微米，传出微动脉直径为7.31±1~0.81微米。乙酰唑胺可显著降低AAD至6.64+/-0.57um，但对AAD无明显影响。速尿逆转乙酰唑胺诱导的AFF-…更严格的限制。Dahl盐敏感(DS)大鼠转化生长因子活性：DS大鼠给予高盐饮食(H：8%氯化钠)和低盐饮食(L：0.3%氯化钠)。SD大鼠和DS/L大鼠的基础AADS相似(8.57±0.43和8.74±0.20微米)。在DS/L大鼠，乙酰唑胺引起传入收缩，速尿逆转乙酰唑胺引起的传入收缩。与SD或DS/L大鼠相比，DS/H大鼠的基础AAD较小(6.09+/-0.49 um)。乙酰唑胺不能降低DS/L大鼠的AAD，速尿使AAD恢复到DS/L大鼠水平。因此，可以认为在DS/H大鼠模型中可能激活了转化生长因子机制。转化生长因子机制中介体的测定：肾间质腺苷、三磷酸腺苷和一氧化氮代谢产物的浓度。观察到转化生长因子介导的肾血管阻力变化与肾间质中三磷酸腺苷浓度呈正相关，从而建立了体内动态评价转化生长因子活性及显示DS/H大鼠转化生长因子活性异常的方法。此外，在转化生长因子机制中，我们还可以选择ATP作为一种介体。基于这些发现，我们相信能够开发治疗肾病的新策略。较少

It is speculated that an abnormal tubulo-glomerular feedback (TGF) activity may induce the nephropathy via renal hemodynamic changes. However, there are no useful technique to evaluate the TGF activity. The purposes of this project are to develop the in vivo dynamic method to evaluate TGF activity, to evaluate the TGF activity in renal disease models, and to determine a possible mediator in TGF mechanisms.1.Development of in vivo dynamic method to evaluate TGF activity : We introduced the intravital CCD-video microscopy that allowed direct in vivo visualization of the renal microcirculation, and measured both afferent and efferent arteriolar diameters in rats. In Sprague-Dawley (SD) rats, the basal afferent and efferent arteriolar diameters were 8.57+/-0.43 and 7.31+1-0.81 um, respectively. Acetazolamide significantly decreased the afferent arteriolar diameter (AAD) to 6.64+/-0.57 um, but did not affect the efferent arteriolar diameter. Furosemide reversed the acetazolamide-induced aff … More erent constriction.2. TGF activity in Dahl salt sensitive (DS) rats : DS rats were given high salt diet (H : 8% NaCl) and low salt diet (L : 0.3% NaCl). Basal AADs were similar between SD and DS/L rats (8.57+/-0.43 and 8.74+/-0.20 um). In DS/L rats, acetazolamide induced the afferent constriction and furosemide reversed the acetazolamide-induced afferent constriction. In contrast to SD or DS/L rats, DS/H rats showed smaller basal AAD (6.09+/-0.49 um). Acetazolamide failed to reduce AAD, but furosemide restored AAD to that in DS/L rat. Thus, it can be considered that TGF mechanisms might be activated in DS/H rats.3. Determination of mediators in TGF mechanisms : The renal interstitial concentration of adenosine, ATP and NO metabolites. We observed the positive correlation between TGF-mediated changes in renal vascular resistance and renal interstitial concentration of ATP.Thus, we could develop the in vivo dynamic method to evaluate TGF activity and show the abnormal TGF activity in DS/H rats. In addition, we could pick up ATP as a mediator in TGF mechanism. Based on these findings we believe to be able to develop the new strategy for the treatment of nephropathy. Less