Connexin 40 is dispensable for vascular renin cell recruitment but is indispensable for vascular baroreceptor control of renin secretion
Connexin 40 is dispensable for vascular renin cell recruitment but is indispensable for vascular baroreceptor control of renin secretion
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DOI：
10.1007/s00424-014-1615-y
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发表时间：
2015-08-01
影响因子：
4.5
通讯作者：
Kurtz, Lisa
中科院分区：
文献类型：
--
作者：
Machura, Katharina;Neubauer, Bjoern;Kurtz, Lisa
肾脏的肾素分泌细胞（RSC）中差距连接蛋白连接蛋白40（Cx40）的缺陷导致RSC的定位从传入小动脉的中膜层转移到肾小球周围的肾小球。RSC的移位与血浆肾素水平升高、肾素分泌的压力控制受损和高血压平行。由于Cx40的缺失导致RSCs向血管外转移和肾素分泌压力调节减弱的原因尚不清楚。因此，我们已经解决了这个问题，如果Cx40是必不可少的化生转化的肾小球前血管平滑肌细胞（SMC）到RSC，如果Cx40是必不可少的压力控制的肾素分泌的RSC位于中层的传入小动脉。在我们的研究中，我们使用缺乏血管紧张素II 1A型（AT（1A））受体的小鼠，其显示出SMC向RSC的显著且可逆的盐敏感性化生转化。将该小鼠系与Cx40缺陷小鼠杂交以获得AT（1A）和Cx40双缺失小鼠。AT（1A）（-/-）Cx40（-/-）小鼠在正常盐（0.3%）条件下，肾小球前血管内膜层和肾小球周围血管均可见RSC。与高血压AT（1A）（-/-）（平均血压112 mmHg）和高血压Cx40（-/-）（平均血压160 mmHg）小鼠相比，AT（1A）（-/-）Cx40（-/-）小鼠血压正常（平均血压130 mmHg）。AT（1A）（-/-）小鼠离体肾脏的肾素分泌压力调节正常，但AT（1A）（-/-）Cx40（-/-）小鼠与Cx40（-/-）小鼠一样，不存在压力调节。低盐饮食（0.02%）增加了中膜层的RSC数量，而高盐饮食（4%）导致中膜层的RSC消失，但肾小球周围的RSC没有消失。血压在AT（1A）（-/-）和AT（1A）（-/-）Cx40（-/-）小鼠中明显对盐敏感，但在后一种基因型中向更高的压力值转移。我们的数据表明，Cx40不是RSC壁内血管定位的必要条件，也不是SMC向RSC可逆性化生转化的必要条件。因此，Cx40（-/-）肾脏中RSC的异位定位更可能是由于细胞间通讯紊乱，而不是肾素-血管紧张素-醛固酮系统慢性过度激活或高血压的结果。此外，我们的研究结果表明，Cx40是一个压力控制的肾素分泌的要求，无论本地化的RSC。
Defects of the gap junction protein connexin 40 (Cx40) in renin-secreting cells (RSCs) of the kidney lead to a shift of the localization of RSCs from the media layer of afferent arterioles to the periglomerular interstitium. The dislocation of RSCs goes in parallel with elevated plasma renin levels, impaired pressure control of renin secretion, and hypertension. The reasons for the extravascular shift of RSCs and the blunted pressure regulation of renin secretion caused by the absence of Cx40 are still unclear. We have therefore addressed the question if Cx40 is essential for the metaplastic transformation of preglomerular vascular smooth muscle cells (SMCs) into RSCs and if Cx40 is essential for the pressure control of renin secretion from RSCs located in the media layer of afferent arterioles. For our study, we used mice lacking the angiotensin II type 1A (AT(1A)) receptors, which display a prominent and reversible salt-sensitive metaplastic transformation of SMCs into RSCs. This mouse line was crossed with Cx40-deficient mice to obtain AT(1A) and Cx40 double deleted mice. The kidneys of AT(1A) (-/-)Cx40(-/-) mice kept on normal salt (0.3 %) displayed RSCs both in the inner media layer of preglomerular vessels and in the periglomerular interstitium. In contrast to hypotensive AT(1A) (-/-) (mean bp syst 112 mmHg) and hypertensive Cx40(-/-) (mean bp syst 160 mmHg) mice AT(1A) (-/-)Cx40(-/-) mice were normotensive(mean bp syst 130 mmHg). Pressure regulation of renin secretion from isolated kidneys was normal in AT(1A) (-/-) mice, but was absent in AT(1A) (-/-)Cx40(-/-) mice alike in Cx40(-/-) mice. Low-salt diet (0.02 %) increased RSC numbers in the media layer, whilst high-salt diet (4 %) caused disappearance of RSCs in the media layer but not in the periglomerular interstitium. Blood pressure was clearly salt sensitive both in AT(1A) (-/-) and in AT(1A) (-/-)Cx40(-/-) mice but was shifted to higher pressure values in the latter genotype. Our data indicate that Cx40 is not a requirement for intramural vascular localization of RSCs nor for reversible metaplastic transformation of SMCs into RSCs. Therefore, the ectopic localization of RSCs in Cx40(-/-) kidneys is more likely due to a disturbed intercellular communication rather than being the result of chronic overactivation of the renin-angiotensin-aldosterone system or hypertension. Moreover, our findings suggest that Cx40 is a requirement for the pressure control of renin secretion irrespective of the localization of RSCs.