Department of Pharmacology, Kagawa University, Kagawa, Japan.
J Am Soc Nephrol. 2012 Nov;23(11):1847-56. doi: 10.1681/ASN.2012010078. Epub 2012 Sep 20.
Patients and animals with renal injury exhibit increased urinary excretion of angiotensinogen. Although increased tubular synthesis of angiotensinogen contributes to the increased excretion, we do not know to what degree glomerular filtration of systemic angiotensinogen, especially through an abnormal glomerular filtration barrier, contributes to the increase in urinary levels. Here, we used multiphoton microscopy to visualize and quantify the glomerular permeability of angiotensinogen in the intact mouse and rat kidney. In healthy mice and Munich-Wistar-Frömter rats at the early stage of glomerulosclerosis, the glomerular sieving coefficient of systemically infused Atto565-labeled human angiotensinogen (Atto565-hAGT), which rodent renin cannot cleave, was only 25% of the glomerular sieving coefficient of albumin, and its urinary excretion was undetectable. In a more advanced phase of kidney disease, the glomerular permeability of Atto565-hAGT was slightly higher but still very low. Furthermore, unlike urinary albumin, the significantly higher urinary excretion of endogenous rat angiotensinogen did not correlate with either the Atto565-hAGT or Atto565-albumin glomerular sieving coefficients. These results strongly suggest that the vast majority of urinary angiotensinogen originates from the tubules rather than glomerular filtration.
患有肾损伤的患者和动物表现出血管紧张素原尿排泄增加。尽管肾小管合成血管紧张素原增加导致排泄增加，但我们不知道全身血管紧张素原肾小球滤过（特别是通过异常肾小球滤过屏障）对尿中水平升高的贡献程度。在这里，我们使用多光子显微镜可视化和定量观察完整小鼠和大鼠肾脏中血管紧张素原的肾小球通透性。在健康小鼠和早期肾小球硬化的慕尼黑 - 维斯塔 - 弗罗默大鼠中，体内输注的 Atto565 标记的人血管紧张素原（Atto565-hAGT）的肾小球筛系数，啮齿动物肾素不能切割，仅为白蛋白的肾小球筛系数的 25％，其尿排泄无法检测到。在肾脏疾病的更晚期，Atto565-hAGT 的肾小球通透性略高，但仍然非常低。此外，与尿白蛋白不同，内源性大鼠血管紧张素原的显著更高的尿排泄与 Atto565-hAGT 或 Atto565-白蛋白肾小球筛系数均无关。这些结果强烈表明，绝大多数尿血管紧张素原来源于肾小管而不是肾小球滤过。
