BACKGROUND Inhibition of angiotensin II (AngII) signaling, a therapeutic mainstay of glomerular kidney diseases, is thought to act primarily through regulating glomerular blood flow and reducing filtration pressure. Although extravascular actions of AngII have been suggested, a direct effect of AngII on podocytes has not been demonstrated in vivo. METHODS To study the effects of AngII on podocyte calcium levels in vivo, we used intravital microscopy of the kidney in mice expressing the calcium indicator protein GCaMP3. RESULTS In healthy animals, podocytes displayed limited responsiveness to AngII stimulation. In contrast, in animals subjected to either adriamycin-induced acute chemical injury or genetic deletion of the podocin-encoding gene Nphs2, the consequent podocyte damage and proteinuria rendered the cells responsive to AngII and resulted in AngII-induced calcium transients in significantly more podocytes. The angiotensin type 1 receptor blocker losartan could fully inhibit this response. Also, responsiveness to AngII was at least partly mediated through the transient receptor potential channel 6, which has been implicated in podocyte calcium handling. Interestingly, loss of a single Nphs2 allele also increased podocytes' responsiveness to AngII signaling. This direct effect of AngII on injured podocytes results in increased calcium transients, which can further aggravate the underlying kidney disease. CONCLUSIONS Our discovery that podocytes become sensitized to AngII-induced calcium signaling upon injury might explain results from large, randomized, controlled trials in which improved renal outcomes occur only in the subgroup of patients with proteinuria, indicating podocyte damage. Our findings also emphasize the need to treat every patient with a glomerular disease with either an angiotensin-converting enzyme inhibitor or an angiotensin type 1 receptor blocker.

中文翻译：

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受伤的足细胞对血管紧张素II诱导的钙信号敏感。

背景技术据认为抑制血管紧张素II（AngII）信号是肾小球肾病的治疗支柱，其作用主要是通过调节肾小球血流量和降低滤过压力。尽管已提出AngII的血管外作用，但尚未在体内证明AngII对足细胞的直接作用。方法为了研究AngII对体内足细胞钙水平的影响，我们使用了肾脏活体显微镜检查了表达钙指示剂蛋白GCaMP3的小鼠的肾脏。结果在健康动物中，足细胞对AngII刺激的反应有限。相反，在遭受阿霉素诱导的急性化学损伤或Podocin编码基因Nphs2的基因缺失的动物中，随之而来的足细胞损伤和蛋白尿使细胞对AngII产生响应，并导致AngII诱导的钙瞬变在更多的足细胞中发生。1型血管紧张素受体阻滞剂氯沙坦可以完全抑制这种反应。而且，对AngII的应答性至少部分地通过瞬时受体电位通道6介导，该通道已经参与足细胞钙的处理。有趣的是，单个Nphs2等位基因的缺失也增加了足细胞对AngII信号的响应能力。AngII对受伤的足细胞的直接作用导致钙瞬变增加，这会进一步加重潜在的肾脏疾病。结论我们的发现：受伤后足细胞对AngII诱导的钙信号敏感，这可能解释了大型，随机，对照试验中，仅在蛋白尿患者亚组中出现肾功能改善，表明足细胞受损。我们的发现还强调需要使用血管紧张素转换酶抑制剂或血管紧张素1型受体阻滞剂治疗每位肾小球疾病的患者。