Giani Jorge F, Janjulia Tea, Kamat Nikhil, Seth Dale M, Blackwell Wendell-Lamar B, Shah Kandarp H, Shen Xiao Z, Fuchs Sebastien, Delpire Eric, Toblli Jorge E, Bernstein Kenneth E, McDonough Alicia A, Gonzalez-Villalobos Romer A
Departments of Biomedical Sciences and Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California;
Department of Cell and Neurobiology, Keck School of Medicine, University of Southern California, Los Angeles, California;
J Am Soc Nephrol. 2014 Dec;25(12):2752-63. doi: 10.1681/ASN.2013091030. Epub 2014 Jul 10.
The kidney is an important source of angiotensin-converting enzyme (ACE) in many species, including humans. However, the specific effects of local ACE on renal function and, by extension, BP control are not completely understood. We previously showed that mice lacking renal ACE, are resistant to the hypertension induced by angiotensin II infusion. Here, we examined the responses of these mice to the low-systemic angiotensin II hypertensive model of nitric oxide synthesis inhibition with L-NAME. In contrast to wild-type mice, mice without renal ACE did not develop hypertension, had lower renal angiotensin II levels, and enhanced natriuresis in response to L-NAME. During L-NAME treatment, the absence of renal ACE was associated with blunted GFR responses; greater reductions in abundance of proximal tubule Na(+)/H(+) exchanger 3, Na(+)/Pi co-transporter 2, phosphorylated Na(+)/K(+)/Cl(-) cotransporter, and phosphorylated Na(+)/Cl(-) cotransporter; and greater reductions in abundance and processing of the γ isoform of the epithelial Na(+) channel. In summary, the presence of ACE in renal tissue facilitates angiotensin II accumulation, GFR reductions, and changes in the expression levels and post-translational modification of sodium transporters that are obligatory for sodium retention and hypertension in response to nitric oxide synthesis inhibition.
在包括人类在内的许多物种中，肾脏是血管紧张素转换酶（ACE）的重要来源。然而，局部ACE对肾功能以及由此延伸的血压控制的具体影响尚未完全明确。我们之前表明，缺乏肾脏ACE的小鼠对血管紧张素II输注诱导的高血压具有抗性。在此，我们研究了这些小鼠对用L-NAME抑制一氧化氮合成的低全身血管紧张素II高血压模型的反应。与野生型小鼠不同，没有肾脏ACE的小鼠不会发生高血压，肾血管紧张素II水平较低，并且对L-NAME的反应增强了利钠作用。在L-NAME治疗期间，缺乏肾脏ACE与肾小球滤过率（GFR）反应减弱有关；近端小管Na(+)/H(+)交换体3、Na(+)/Pi共转运体2、磷酸化的Na(+)/K(+)/Cl(-)共转运体和磷酸化的Na(+)/Cl(-)共转运体的丰度有更大程度的降低；以及上皮Na(+)通道γ亚型的丰度和加工有更大程度的降低。总之，肾脏组织中ACE的存在促进了血管紧张素II的积累、GFR降低以及钠转运体表达水平和翻译后修饰的变化，这些变化对于响应一氧化氮合成抑制时的钠潴留和高血压是必不可少的。
