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.

足细胞中的脂质积累是糖尿病肾病 (DKD) 的主要决定因素，通过介导足细胞脂质代谢来识别潜在的治疗靶点具有临床重要性。本研究旨在阐明JAML（连接粘附分子样蛋白）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，发现足细胞特异性缺失Jaml在两种不同的糖尿病小鼠模型中改善足细胞损伤和蛋白尿。我们进一步证明了 JAML 在通过 SIRT1 介导的 SREBP1 信号传导调节足细胞脂质代谢中的新作用。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，我们观察到 JAML 在患有 DKD 和其他类型蛋白尿肾病的受试者的肾小球中的表达较高，并且 JAML 的水平与脂质积累和肾小球滤过率相关，表明 JAML 可能是蛋白尿肾病的有吸引力的治疗靶点疾病。