Feng Wenguang, Chumley Phillip, Prieto Minolfa C, Miyada Kayoko, Seth Dale M, Fatima Huma, Hua Ping, Rezonzew Gabriel, Sanders Paul W, Jaimes Edgar A
From the Division of Nephrology (W.F., P.C., P.H., G.R., P.W.S.) and Department of Pathology (H.F.), University of Alabama at Birmingham; Department of Physiology, Tulane University, New Orleans, LA (M.C.P., K.M., D.M.S.); Nephrology Section, VA Medical Center, Birmingham, AL (P.W.S., E.A.J.); and Renal Service, Memorial Sloan Kettering Cancer Center, New York, NY (E.A.J.).
Hypertension. 2015 Apr;65(4):813-20. doi: 10.1161/HYPERTENSIONAHA.114.04533. Epub 2015 Jan 26.
Transcription factor E26 transformation-specific sequence-1 (ETS-1) is a transcription factor that regulates the expression of a variety of genes, including growth factors, chemokines, and adhesion molecules. We recently demonstrated that angiotensin II increases the glomerular expression of ETS-1 and that blockade of ETS-1 ameliorates the profibrotic and proinflammatory effects of angiotensin II. The Dahl salt-sensitive rat is a paradigm of salt-sensitive hypertension associated with local activation of the renin-angiotensin system. In these studies, we determined whether: (1) salt-sensitive hypertension is associated with renal expression of ETS-1 and (2) ETS-1 participates in the development of end-organ injury in salt-sensitive hypertension. Dahl salt-sensitive rats were fed a normal-salt diet (0.5% NaCl diet) or a high-salt diet (4% NaCl) for 4 weeks. Separate groups on high-salt diet received an ETS-1 dominant-negative peptide (10 mg/kg/d), an inactive ETS-1 mutant peptide (10 mg/kg/d), the angiotensin II type 1 receptor blocker candesartan (10 mg/kg/d), or the combination high-salt diet/dominant-negative peptide/angiotensin II type 1 receptor blocker for 4 weeks. High-salt diet rats had a significant increase in the glomerular expression of the phosphorylated ETS-1 that was prevented by angiotensin II type 1 receptor blocker. ETS-1 blockade reduced proteinuria, glomerular injury score, fibronectin expression, urinary transforming growth factor-β excretion, and macrophage infiltration. Angiotensin II type 1 receptor blocker reduced proteinuria, glomerular injury score, and macrophage infiltration, whereas concomitant ETS-1 blockade and angiotensin II type 1 receptor blocker had additive effects and reduced interstitial fibrosis. Our studies demonstrated that salt-sensitive hypertension results in increased glomerular expression of phosphorylated ETS-1 and suggested that ETS-1 plays an important role in the pathogenesis of end-organ injury in salt-sensitive hypertension.
转录因子E26转化特异性序列-1（ETS-1）是一种转录因子，可调节多种基因的表达，包括生长因子、趋化因子和黏附分子。我们最近证明，血管紧张素II可增加ETS-1在肾小球的表达，而阻断ETS-1可改善血管紧张素II的促纤维化和促炎作用。Dahl盐敏感大鼠是与肾素-血管紧张素系统局部激活相关的盐敏感性高血压的范例。在这些研究中，我们确定：（1）盐敏感性高血压是否与ETS-1在肾脏的表达相关；（2）ETS-1是否参与盐敏感性高血压终末器官损伤的发生发展。将Dahl盐敏感大鼠分为两组，分别给予正常盐饮食（0.5% NaCl饮食）或高盐饮食（4% NaCl），持续4周。高盐饮食组中的不同亚组分别接受ETS-1显性负性肽（10 mg/kg/d）、无活性的ETS-1突变肽（10 mg/kg/d）、血管紧张素II 1型受体阻滞剂坎地沙坦（10 mg/kg/d），或高盐饮食/显性负性肽/血管紧张素II 1型受体阻滞剂联合用药，持续4周。高盐饮食大鼠肾小球中磷酸化ETS-
