Injured Podocytes Are Sensitized to Angiotensin II-Induced Calcium Signaling
Injured Podocytes Are Sensitized to Angiotensin II-Induced Calcium Signaling
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DOI：
10.1681/asn.2019020109
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发表时间：
2020-03-01
影响因子：
13.6
通讯作者：
Hackl, Matthias J.
中科院分区：
文献类型：
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作者：
Binz-Lotter, Julia;Juengst, Christian;Hackl, Matthias J.
背景血管紧张素II（AngII）信号传导的抑制是肾小球肾脏疾病的主要治疗手段，被认为主要通过调节肾小球血流和降低滤过压发挥作用。虽然血管外的行动，血管紧张素II对足细胞的直接影响还没有被证明在vivo.Methods在体内研究血管紧张素II对足细胞的钙水平的影响，我们用活体显微镜下的小鼠肾脏表达钙指示蛋白GCaMP 3。相比之下，在遭受阿霉素诱导的急性化学损伤或podocin编码基因Nphs 2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产生反应，并导致AngII诱导的钙瞬变在显着更多的足细胞中。血管紧张素1受体阻断剂氯沙坦可完全抑制这种反应。此外，对AngII的反应性至少部分通过瞬时受体电位通道6介导，该通道与足细胞钙处理有关。有趣的是，单个Nphs2等位基因的缺失也增加了足细胞对AngII信号传导的反应性。AngII对受损足细胞的直接影响导致钙瞬变增加，这可能会进一步加重潜在的肾脏疾病。结论我们发现足细胞对AngII诱导的钙信号在损伤后变得敏感，这可能解释了大型随机对照试验的结果，在这些试验中，改善的肾脏预后仅发生在蛋白尿患者亚组中，表明足细胞损伤。我们的研究结果也强调，需要治疗每一个肾小球疾病的患者与血管紧张素转换酶抑制剂或血管紧张素1型受体阻滞剂。
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 Angll 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 podocinencoding gene Nphs2, the consequent podocyte damage and proteinuria rendered the cells responsive to Angll 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.