Department of Nephrology and Rheumatology, Gunma University Graduate School of Medicine, Gunma, Japan.
Kidney Disease Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, United States.
Am J Physiol Renal Physiol. 2023 Jul 1;325(1):F121-F133. doi: 10.1152/ajprenal.00313.2022. Epub 2023 May 11.
Transforming growth factor (TGF)-β1 contributes to podocyte injury in various glomerular diseases, including diabetic kidney disease, probably at least in part by attenuating the expression of Wilms' tumor 1 (WT1). However, the precise mechanisms remain to be defined. We performed miRNA microarray analysis in a human podocyte cell line cultured with TGF-β1 to examine the roles of miRNAs in podocyte damage. The microarray analysis identified miR-143-3p as the miRNA with the greatest increase following exposure to TGF-β1. Quantitative RT-PCR confirmed a significant increase in the miR-143-3p/145-5p cluster in TGF-β1-supplemented cultured podocytes and demonstrated upregulation of miR-143-3p in the glomeruli of mice with type 2 diabetes. Ectopic expression of miR-143-3p and miR-145-5p suppressed WT1 expression in cultured podocytes. Furthermore, inhibition of Smad or mammalian target of rapamycin signaling each partially reversed the TGF-β1-induced increase in miR-143-3p/145-5p and decrease in WT1. In conclusion, TGF-β1 induces expression of miR-143-3p/145-5p in part through Smad and mammalian target of rapamycin pathways, and miR-143-3p/145-5p reduces expression of WT1 in cultured human podocytes. miR-143-3p/145-5p may contribute to TGF-β1-induced podocyte injury. This study by miRNA microarray analysis demonstrated that miR-143-3p expression was upregulated in cultured human podocytes following exposure to transforming growth factor (TGF)-β1. Furthermore, we report that the miR-143/145 cluster contributes to decreased expression of Wilms' tumor 1, which represents a possible mechanism for podocyte injury induced by TGF-β1. This study is important because it presents a novel mechanism for TGF-β-associated glomerular diseases, including diabetic kidney disease (DKD), and suggests potential therapeutic strategies targeting miR-143-3p/145-5p.
转化生长因子 (TGF)-β1 参与多种肾小球疾病（包括糖尿病肾病）的足细胞损伤，可能至少部分通过减弱 Wilms 肿瘤 1（WT1）的表达来实现。然而，确切的机制仍有待确定。我们在 TGF-β1 培养的人足细胞系中进行 miRNA 微阵列分析，以研究 miRNA 在足细胞损伤中的作用。微阵列分析确定 miR-143-3p 是 TGF-β1 暴露后增加最多的 miRNA。定量 RT-PCR 证实 TGF-β1 补充培养的足细胞中 miR-143-3p/145-5p 簇显著增加，并证明 2 型糖尿病小鼠肾小球中 miR-143-3p 上调。miR-143-3p 和 miR-145-5p 的异位表达抑制了培养的足细胞中的 WT1 表达。此外，抑制 Smad 或哺乳动物雷帕霉素靶蛋白信号通路均可部分逆转 TGF-β1 诱导的 miR-143-3p/145-5p 增加和 WT1 减少。总之，TGF-β1 通过 Smad 和哺乳动物雷帕霉素靶蛋白途径诱导 miR-143-3p/145-5p 的表达，miR-143-3p/145-5p 降低培养的人足细胞中 WT1 的表达。miR-143-3p/145-5p 可能导致 TGF-β1 诱导的足细胞损伤。本 miRNA 微阵列分析研究表明，TGF-β1 暴露后培养的人足细胞中 miR-143-3p 的表达上调。此外，我们报告 miR-143/145 簇有助于降低 Wilms 肿瘤 1 的表达，这代表了 TGF-β1 诱导的足细胞损伤的一种可能机制。本研究很重要，因为它提出了 TGF-β 相关肾小球疾病（包括糖尿病肾病）的一种新机制，并表明针对 miR-143-3p/145-5p 的潜在治疗策略。
