Feng Wenguang, Guan Zhengrong, Xing Dongqi, Li Xingsheng, Ying Wei-Zhong, Remedies Colton E, Inscho Edward W, Sanders Paul W
Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
Kidney Int. 2020 Mar;97(3):528-537. doi: 10.1016/j.kint.2019.09.025. Epub 2019 Oct 22.
Prior studies reported that haploinsufficiency of the transcription factor ETS-1 is renoprotective in Dahl salt-sensitive rats, but the mechanism is unclear. Here, we tested whether ETS-1 is involved in hypertension-induced renal microvascular pathology and autoregulatory impairment. Hypertension was induced in salt-sensitive rats and salt-sensitive rats that are heterozygous with 1 wild-type or reference allele of Ets1 (SS) by feeding a diet containing 4% sodium chloride for 1 week. Increases in blood pressure did not differ. However, phosphorylated ETS-1 increased in afferent arterioles of hypertensive salt-sensitive rats, but not in hypertensive SS rats. Afferent arterioles of hypertensive salt-sensitive rats showed increased monocyte chemotactic protein-1 expression and infiltration of CD68 positive monocytes/macrophages. Isolated kidney microvessels showed increased mRNA expression of vascular cell adhesion molecule, intercellular adhesion molecule, P-selectin, fibronectin, transforming growth factor-β, and collagen I in hypertensive salt-sensitive rats compared with hypertensive SS rats. Using the in vitro blood-perfused juxtamedullary nephron preparation, pressure-mediated afferent arteriolar responses were significantly blunted in hypertensive salt-sensitive rats compared to hypertensive SS rats. Over a 65-170 mm Hg pressure range tested baseline arteriolar diameters averaged 15.1 μm and remained between 107% and 89% of baseline diameter in hypertensive salt-sensitive rats vs. 114% and 73% in hypertensive SS rats (significantly different). Thus, ETS-1 participates in renal arteriolar pathology and autoregulation and thereby is involved in hypertension-mediated kidney injury in salt-sensitive rats.
先前的研究报道，转录因子ETS-1单倍剂量不足对 Dahl 盐敏感大鼠具有肾脏保护作用，但其机制尚不清楚。在此，我们测试了ETS-1是否参与高血压诱导的肾微血管病变和自身调节功能障碍。通过喂食含4%氯化钠的饲料1周，在盐敏感大鼠和携带1个野生型或Ets1参考等位基因的杂合盐敏感大鼠（SS）中诱导高血压。血压升高情况并无差异。然而，高血压盐敏感大鼠的入球小动脉中磷酸化ETS-1增加，而高血压SS大鼠中则未增加。高血压盐敏感大鼠的入球小动脉显示单核细胞趋化蛋白-1表达增加以及CD68阳性单核细胞/巨噬细胞浸润。与高血压SS大鼠相比，高血压盐敏感大鼠分离的肾微血管显示血管细胞黏附分子、细胞间黏附分子、P-选择素、纤连蛋白、转化生长因子-β和I型胶原的mRNA表达增加。使用体外血液灌注的近髓肾单位制备方法，与高血压SS大鼠相比，高血压盐敏感大鼠压力介导的入球小动脉反应明显减弱。在65 - 170 mmHg的测试压力范围内，高血压盐敏感大鼠的基线小动脉直径平均为15.1μm，在压力变化时保持在基线直径的107%至89%之间，而高血压SS大鼠则为114%至73%（差异显著）。因此，ETS-1参与肾小动脉病变和自身调节，从而参与盐敏感大鼠高血压介导的肾损伤。
