Department of Pediatrics Yale University School of Medicine New Haven CT.
Vascular Biology and Therapeutics Program Yale University School of Medicine New Haven CT.
J Am Heart Assoc. 2021 Aug 3;10(15):e019437. doi: 10.1161/JAHA.120.019437. Epub 2021 Jul 26.
Background Proteinuria and glomerular segmental fibrosis are inevitable complications of diabetic nephropathy though their mechanisms are poorly understood. Understanding the clinical characteristics and pathogenesis of proteinuria and glomerular segmental fibrosis in diabetic nephropathy is, therefore, urgently needed for patient management of this severe disease. Methods and Results Diabetes mellitus was induced in podocyte-specific glucocorticoid receptor knockout (GR) mice and control littermates by administration of streptozotocin. Primary podocytes were isolated and subjected to analysis of Wnt signaling and fatty acid metabolism. Conditioned media from primary podocytes was transferred to glomerular endothelial cells. Histologic analysis of kidneys from diabetic GR mice showed worsened fibrosis, increased collagen deposition, and glomerulomegaly indicating severe glomerular fibrosis. Higher expression of transforming growth factor-βR1 and β-catenin and suppressed expression of carnitine palmitoyltransferase 1A in nephrin-positive cells were found in the kidneys of diabetic GR mice. Podocytes isolated from diabetic GR mice demonstrated significantly higher profibrotic gene expression and suppressed fatty acid oxidation compared with controls. Administration of a Wnt inhibitor significantly improved the fibrotic features in GR mice. The glomerular endothelium of diabetic GR mice demonstrated the features of endothelial-to-mesenchymal transition. Moreover, endothelial cells treated with conditioned media from podocytes lacking GR showed increased expression of α-smooth muscle actin, transforming growth factor-βR1 and β-catenin levels. Conclusions These data demonstrate that loss of podocyte GR leads to upregulation of Wnt signaling and disruption in fatty acid metabolism. Podocyte-endothelial cell crosstalk, mediated through GR, is important for glomerular homeostasis, and its disruption likely contributes to diabetic nephropathy.
蛋白尿和肾小球节段性纤维化是糖尿病肾病不可避免的并发症，但其机制尚不清楚。因此，了解糖尿病肾病中蛋白尿和肾小球节段性纤维化的临床特征和发病机制，对于这种严重疾病患者的管理是迫切需要的。
通过给予链脲佐菌素诱导足细胞特异性糖皮质激素受体敲除（GR）小鼠和对照同窝仔鼠糖尿病。分离原代足细胞并进行 Wnt 信号和脂肪酸代谢分析。将原代足细胞的条件培养基转染至肾小球内皮细胞。糖尿病 GR 小鼠肾脏的组织学分析显示纤维化加重、胶原沉积增加和肾小球肿大，表明严重的肾小球纤维化。糖尿病 GR 小鼠肾脏中肾小球内足突细胞中转化生长因子-βR1 和 β-catenin 表达增加，肉毒碱棕榈酰转移酶 1A 表达受抑制。从糖尿病 GR 小鼠分离的足细胞表现出明显更高的致纤维化基因表达和抑制的脂肪酸氧化。Wnt 抑制剂的给药显著改善了 GR 小鼠的纤维化特征。糖尿病 GR 小鼠的肾小球内皮细胞表现出内皮-间充质转化的特征。此外，用缺乏 GR 的足细胞的条件培养基处理的内皮细胞显示出α-平滑肌肌动蛋白、转化生长因子-βR1 和 β-catenin 水平的表达增加。
这些数据表明，足细胞 GR 的缺失导致 Wnt 信号的上调和脂肪酸代谢的破坏。足细胞-内皮细胞的串扰，通过 GR 介导，对肾小球稳态很重要，其破坏可能导致糖尿病肾病。
