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Upregulated LRRC55 promotes BK channel activation and aggravates cell injury in podocytes.

上调的LRRC55促进BK通道激活并加重足细胞的细胞损伤。

  • 影响因子:9.83
  • DOI:10.1084/jem.20192373
  • 作者列表:"Hu S","Han R","Chen L","Qin W","Xu X","Shi J","Zhu X","Zhang M","Zeng C","Tang Z","Bao H","Liu Z
  • 发表时间:2021-03-01
Abstract

:Podocyte injury is a common hallmark in various glomerular diseases. The level of LRRC55 was increased in podocytes of patients with focal segmental glomerulosclerosis (FSGS), diabetic nephropathy (DN), and membranous nephropathy (MN). Upregulated LRRC55 and increased intracellular Ca2+ led to BK channel activation and the loss of intracellular potassium, resulting in apoptosome formation and caspase-3 activation in angiotensin II (Ang II)-treated podocytes. Knockout of Lrrc55 or the BK channel prevented the BK current and ameliorated podocyte injury in Ang II-treated mice. Upstream, NFATc3 regulated the expression of LRRC55. Increased LRRC55 expression in podocytes was also evident in animal models of FSGS, DN, and MN. Treatment with losartan or LRRC55 siRNA suppressed LRRC55 expression, prevented BK channel activation, and attenuated podocyte injury in animal models of FSGS, DN, and MN. In conclusion, upregulated LRRC55 promotes BK channel activation and aggravates cell injury in podocytes in FSGS, DN, and MN. LRRC55 inhibition may represent a new therapeutic approach for podocyte injury.

摘要

: 足细胞损伤是多种肾小球疾病的共同标志。局灶节段性肾小球硬化 (FSGS) 、糖尿病肾病 (DN) 和膜性肾病 (MN) 患者足细胞LRRC55水平升高。上调LRRC55和增加细胞内Ca2 + 导致BK通道激活和细胞内钾损失,导致血管紧张素II (Ang II) 处理的足细胞中凋亡体形成和caspase-3激活。敲除Lrrc55或BK通道可预防BK电流并改善Ang II治疗小鼠的足细胞损伤。上游,NFATc3调控lrrc55的表达。足细胞中LRRC55表达增加在FSGS、DN和MN的动物模型中也很明显。在FSGS、DN和MN动物模型中,氯沙坦或LRRC55 siRNA治疗抑制LRRC55表达,阻止BK通道激活,并减轻足细胞损伤。总之,上调的LRRC55促进BK通道激活,加重FSGS、DN和MN足细胞的细胞损伤。LRRC55抑制可能代表了足细胞损伤的一种新的治疗方法。

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