The Key Laboratory of Infection and Immunity of Shandong Province, Department of Pharmacology, School of Basic Medical Sciences, Shandong University, Jinan 250012, China.
Intensive Care Unit, Shandong Provincial Qianfoshan Hospital, the First Hospital Affiliated with Shandong First Medical University, Jinan 250014, China.
Cell Metab. 2020 Dec 1;32(6):1052-1062.e8. doi: 10.1016/j.cmet.2020.10.019. Epub 2020 Nov 12.
Lipid accumulation in podocytes is a major determinant of diabetic kidney disease (DKD) and identification of potential therapeutic targets by mediating podocyte lipid metabolism has clinical importance. This study was to elucidate the role of JAML (junctional adhesion molecule-like protein) in the pathogenesis of DKD. We first confirmed the expression of JAML in podocytes and found that podocyte-specific deletion of Jaml ameliorated podocyte injury and proteinuria in two different models of diabetic mice. We further demonstrated a novel role of JAML in regulating podocyte lipid metabolism through SIRT1-mediated SREBP1 signaling. Similar results were also found in mice with adriamycin-induced nephropathy. Importantly, we observed a higher expression of JAML in glomeruli from subjects with DKD and other types of proteinuric kidney diseases, and the level of JAML was correlated with lipid accumulation and glomerular filtration rate, suggesting that JAML may be an attractive therapeutic target for proteinuric kidney disease.
足细胞内脂质堆积是糖尿病肾病（DKD）的一个主要决定因素，通过调节足细胞脂质代谢来确定潜在的治疗靶点具有重要的临床意义。本研究旨在阐明 JAML（连接黏附分子样蛋白）在 DKD 发病机制中的作用。我们首先证实了 JAML 在足细胞中的表达，并发现 Jaml 的足细胞特异性缺失可改善两种不同糖尿病小鼠模型中的足细胞损伤和蛋白尿。我们进一步证明了 JAML 通过 SIRT1 介导的 SREBP1 信号通路调节足细胞脂质代谢的新作用。在阿霉素诱导的肾病小鼠中也发现了类似的结果。重要的是，我们在 DKD 患者和其他类型的蛋白尿性肾病患者的肾小球中观察到 JAML 的表达升高，并且 JAML 的水平与脂质堆积和肾小球滤过率相关，提示 JAML 可能是一种有吸引力的蛋白尿性肾病治疗靶点。
