Long noncoding RNA SNHG5 promotes podocyte injury via the microRNA-26a-5p/TRPC6 pathway in diabetic nephropathy.
Long noncoding RNA SNHG5 promotes podocyte injury via the microRNA-26a-5p/TRPC6 pathway in diabetic nephropathy.
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DOI：
10.1016/j.jbc.2022.102605
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发表时间：
2022-12
影响因子：
4.8
通讯作者：
Ma, Rui-Xia
中科院分区：
文献类型：
--
作者：
Zhou, Yan;Li, Zuo-Lin;Ding, Lin;Zhang, Xing-Jian;Liu, Nan -Chi;Liu, Shan -Shan;Wang, Yan-Fei;Ma, Rui-Xia
足细胞损伤是糖尿病肾病（DN）的特征性病理标志。然而，DN中足细胞损伤的确切机制尚不完全清楚。本研究使用db/db小鼠和永生化小鼠足细胞进行。采用高通量测序技术鉴定db/db小鼠肾脏中差异表达的长链非编码RNA。使用针对长非编码RNA小核仁RNA宿主基因5（SNHG 5）或microRNA-26 a-5 p（miR-26 a-5 p）的慢病毒shRNA agomir治疗db/db小鼠以调节SNHG 5/miR-26 a-5 p通路。本研究发现，在DN条件下，受损足细胞中瞬时受体电位典型6型（TRPC 6）的表达显著增加，这与miR-26 a-5 p的显著降低有关。我们确定miR-26 a-5 p过表达通过与Trpc 6的3′-UTR结合来改善DN中足细胞的损伤，这通过miR-26 a-5 p模拟物显著降低荧光素酶报告基因的活性来证明。然后，通过荧光素酶活性、RNA免疫沉淀和RNA pull-down实验，证实SNHG 5在DN足细胞和肾脏中表达上调，并直接与miR-26 a-5 p发生海绵状反应。SNHG 5的敲低在体外减轻足细胞损伤，伴随着miR-26 a-5 p的表达增加和TRPC 6的表达减少，表明SNHG 5通过控制miR-26 a-5 p/TRPC 6途径促进足细胞损伤。此外，SNHG 5的敲低在体内保护足细胞损伤和DN的进展。总之，SNHG 5通过miR-26 a-5 p/TRPC 6途径促进DN中足细胞损伤。我们的研究结果为足细胞损伤的病理生理学和DN的潜在新治疗策略提供了新的见解。
Podocyte injury is a characteristic pathological hallmark of diabetic nephropathy (DN). However, the exact mechanism of podocyte injury in DN is incompletely understood. This study was conducted using db/db mice and immortalized mouse podocytes. High-throughput sequencing was used to identify the differentially expressed long noncoding RNAs in kidney of db/db mice. The lentiviral shRNA directed against long noncoding RNA small nucleolar RNA host gene 5 (SNHG5) or microRNA-26a-5p (miR-26a-5p) agomir was used to treat db/db mice to regulate the SNHG5/miR-26a-5p pathway. Here, we found that the expression of transient receptor potential canonical type 6 (TRPC6) was significantly increased in injured podocytes under the condition of DN, which was associated with markedly decreased miR-26a-5p. We determined that miR-26a-5p overexpression ameliorated podocyte injury in DN via binding to 3′-UTR of Trpc6, as evidenced by the markedly reduced activity of luciferase reporters by miR-26a-5p mimic. Then, the upregulated SNHG5 in podocytes and kidney in DN was identified, and it was proved to sponge to miR-26a-5p directly using luciferase activity, RNA immunoprecipitation, and RNA pull-down assay. Knockdown of SNHG5 attenuated podocyte injury in vitro, accompanied by an increased expression of miR-26a-5p and decreased expression of TRPC6, demonstrating that SNHG5 promoted podocyte injury by controlling the miR-26a-5p/TRPC6 pathway. Moreover, knockdown of SNHG5 protects against podocyte injury and progression of DN in vivo. In conclusion, SNHG5 promotes podocyte injury via the miR-26a-5p/TRPC6 pathway in DN. Our findings provide novel insights into the pathophysiology of podocyte injury and a potential new therapeutic strategy for DN.
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