Division of Nephrology, University of Utah Health Sciences Center, 1900 East 30 North, Salt Lake City, UT 84132, USA.
BMC Nephrol. 2012 Dec 5;13:166. doi: 10.1186/1471-2369-13-166.
Endothelin, via endothelin A receptors (ETA), exerts multiple pathologic effects that contribute to disease pathogenesis throughout the body. ETA antagonists ameliorate many experimental diseases and have been extensively utilized in clinical trials. The utility of ETA blockers has been greatly limited, however, by fluid retention, sometimes leading to heart failure or death. To begin to examine this issue, the effect of genetic disruption of ETA in the nephron on blood pressure and salt handling was determined.
Mice were generated with doxycycline-inducible nephron-specific ETA deletion using Pax8-rtTA and LC-1 transgenes on the background of homozygous loxP-flanked ETA alleles. Arterial pressure, Na metabolism and measures of body fluid volume status (hematocrit and impedance plethysmography) were assessed.
Absence of nephron ETA did not alter arterial pressure whether mice were ingesting a normal or high Na diet. Nephron ETA disruption did not detectably affect 24 hr Na excretion or urine volume regardless of Na intake. However, mice with nephron ETA knockout that were fed a high Na diet had mild fluid retention as evidenced by an increase in body weight and a fall in hematocrit.
Genetic deletion of nephron ETA causes very modest fluid retention that does not alter arterial pressure. Nephron ETA, under normal conditions, likely do not play a major role in regulation of Na excretion or systemic hemodynamics.
内皮素通过内皮素 A 受体（ETA）发挥多种病理作用，这些作用有助于全身疾病的发病机制。ETA 拮抗剂改善了许多实验性疾病，并已广泛应用于临床试验。然而，ETA 阻滞剂的应用受到限制，因为它会导致液体潴留，有时会导致心力衰竭或死亡。为了开始研究这个问题，研究人员确定了内皮素在肾单位中的遗传缺失对血压和盐处理的影响。
使用 Pax8-rtTA 和 LC-1 转基因，在同源性loxP 侧翼 ETA 等位基因的背景下，生成可诱导内皮素 A 受体（ETA）在肾单位中特异性缺失的小鼠。评估了动脉压、Na 代谢和体液容量状态的测量（血细胞比容和阻抗体积描记法）。
无论小鼠摄入正常或高 Na 饮食，肾单位 ETA 的缺失都不会改变动脉压。无论 Na 摄入量如何，肾单位 ETA 缺失都不会明显影响 24 小时 Na 排泄或尿量。然而，在高盐饮食下，肾单位 ETA 敲除的小鼠有轻度的液体潴留，表现为体重增加和血细胞比容下降。
肾单位内皮素 A 受体的基因缺失导致非常轻微的液体潴留，不会改变动脉压。在正常情况下，肾单位内皮素 A 受体可能不会在 Na 排泄或全身血液动力学的调节中发挥主要作用。
