Kessler Sean P, Hashimoto Seiji, Senanayake Preenie S, Gaughan Christina, Sen Ganes C, Schnermann Jurgen
Department of Molecular Genetics, Lerner Research Institute, Cleveland, OH 44195, USA.
J Am Soc Nephrol. 2005 Dec;16(12):3535-42. doi: 10.1681/ASN.2005020151. Epub 2005 Oct 12.
Angiotensin-converting enzyme (ACE) null mice display aberrant renal pathology. Inadequate formation of angiotensin II (Ang II) results in hypotension, loss of fluid homeostasis, lack of urine concentration, and failure to regulate GFR through the tubuloglomerular feedback (TGF) mechanism. For examining the tissue-specific role of ACE in renal structure and regulation of renal filtrate formation, single-nephron GFR, proximal tubular fluid reabsorption, and TGF responsiveness were determined in mice that expressed ACE in only one tissue. Maximum TGF responses in mice that expressed somatic ACE (sACE) in proximal tubule cells (Gs strain) or germinal ACE in the serum (Pg strain) were reduced significantly compared with wild-type (WT) mice. In contrast, TGF responses in mice that expressed sACE in vascular endothelial cells (Ts strain) were not different from control. Single-nephron GFR was reduced in Ts compared with WT mice, but fractional reabsorption and therefore glomerulotubular balance were not distinguishable. BP responses to exogenous Ang I were diminished in Ts, Gs, and Pg mice, whereas those to Ang II were the same in the different strains. Plasma and renal tissue Ang I of all transgenic mouse strains was significantly higher than WT, whereas Ang II levels were generally lower; aldosterone levels were significantly lower than WT in Ts mice but not in the two other transgenic strains. Our results demonstrate that vascular expression of sACE can largely but not completely restore TGF regulation of GFR. Proximal fluid reabsorption in the chronic absence of proximal tubule ACE is normal.
血管紧张素转换酶（ACE）基因敲除小鼠表现出异常的肾脏病理变化。血管紧张素II（Ang II）生成不足导致低血压、液体稳态丧失、尿液浓缩功能缺失以及无法通过肾小管-肾小球反馈（TGF）机制调节肾小球滤过率（GFR）。为了研究ACE在肾脏结构和肾滤液生成调节中的组织特异性作用，我们测定了仅在一种组织中表达ACE的小鼠的单肾单位GFR、近端肾小管液体重吸收以及TGF反应性。与野生型（WT）小鼠相比，在近端小管细胞中表达体细胞ACE（sACE）的小鼠（Gs品系）或血清中表达生殖细胞ACE的小鼠（Pg品系）的最大TGF反应显著降低。相比之下，在血管内皮细胞中表达sACE的小鼠（Ts品系）的TGF反应与对照组无差异。与WT小鼠相比，Ts小鼠的单肾单位GFR降低，但分数重吸收以及因此的肾小球-肾小管平衡并无差异。Ts、Gs和Pg小鼠对外源性Ang I的血压反应减弱，而对Ang II的反应在不同品系中相同。所有转基因小鼠品系的血浆和肾脏组织Ang I均显著高于WT，而Ang II水平通常较低；Ts小鼠的醛固酮水平显著低于WT，但在另外两个转基因品系中并非如此。我们的结果表明，sACE的血管表达可以在很大程度上但不能完全恢复TGF对GFR的调节。在长期缺乏近端小管ACE的情况下，近端液体重吸收正常。
