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LRRC55 上调促进 BK 通道激活并加重足细胞损伤。

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

机构信息

National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China.

National Standard Laboratory of Pharmacology for Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China.

出版信息

J Exp Med. 2021 Mar 1;218(3). doi: 10.1084/jem.20192373.

DOI:10.1084/jem.20192373
PMID:33346797
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7756252/
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

足细胞损伤是各种肾小球疾病的共同特征。局灶节段性肾小球硬化症（FSGS）、糖尿病肾病（DN）和膜性肾病（MN）患者的足细胞中 LRRC55 水平升高。LRRC55 的上调和细胞内 Ca2+的增加导致 BK 通道激活和细胞内钾丢失，从而在血管紧张素 II（Ang II）处理的足细胞中形成凋亡小体和 caspase-3 激活。Lrrc55 或 BK 通道的敲除可防止 BK 电流，并改善 Ang II 处理的小鼠的足细胞损伤。上游 NFATc3 调节 LRRC55 的表达。LRRC55 在 FSGS、DN 和 MN 动物模型中的足细胞中也有明显表达。用氯沙坦或 LRRC55 siRNA 治疗可抑制 LRRC55 的表达，防止 BK 通道激活，并减轻 FSGS、DN 和 MN 动物模型中的足细胞损伤。总之，LRRC55 的上调促进了 FSGS、DN 和 MN 中足细胞的 BK 通道激活和加重细胞损伤。LRRC55 抑制可能代表足细胞损伤的一种新的治疗方法。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/27b3/7756252/d20eb03c7549/JEM_20192373_FigS2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/27b3/7756252/35d5ffb21880/JEM_20192373_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/27b3/7756252/fc74b66cb1ab/JEM_20192373_FigS1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/27b3/7756252/53e3d11ccd5e/JEM_20192373_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/27b3/7756252/d20eb03c7549/JEM_20192373_FigS2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/27b3/7756252/35d5ffb21880/JEM_20192373_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/27b3/7756252/fc74b66cb1ab/JEM_20192373_FigS1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/27b3/7756252/53e3d11ccd5e/JEM_20192373_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/27b3/7756252/d20eb03c7549/JEM_20192373_FigS2.jpg

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