NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital, And Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin 300134, China.
Wuhan Third Hospital, Tongren Hospital of Wuhan University, Wuhan 430070, China.
J Diabetes Res. 2022 Oct 25;2022:3411123. doi: 10.1155/2022/3411123. eCollection 2022.
Patients with diabetic ketosis often exhibit albuminuria. We previously found that acute hyperglycaemia can cause nephrotoxic injury. Here, we explored whether an excessive ketone body level causes kidney injury and the potential underlying mechanism.
Fifty-six type 2 diabetes without ketosis (NDK group), 81 type 2 diabetes with ketosis (DK group), and 38 healthy controls (NC group) were enrolled. Clinical data were collected before and after controlling diabetic ketosis. Beta-hydroxybutyric acid (BOHB), an AKT activator, an AKT inhibitor, or plasmids encoding DAB2 were transformed into human renal proximal tubule epithelial cells (HK-2 cells).
The urinary albumin-to-creatinine ratio (ACR), transferrin (TF), immunoglobulin G (IgG), Beta2-microglobulin (2-MG), retinol-binding protein (RBP), N-acetyl-beta-glucosaminidase (NAG), and Beta-galactosidase (GAL) were higher in the DK than NC and NDK groups. The proportion of patients with an increased urinary level of TF, IgG, 2-MG, RBP, NAG, or GAL was higher in the DK group too. After controlling ketosis, urinary microalbumin, TF, IgG, 2-MG, and RBP decreased significantly. In HK-2 cells, albumin endocytosis and megalin expression decreased with increasing BOHB concentration. Compared with BOHB treatment, BOHB with AKT activator significantly increased the DAB2, megalin levels and albumin endocytosis; the AKT inhibitor treatment exhibited the opposite effects. Compared with BOHB treatment, megalin expression and albumin endocytosis were significantly increased after BOHB with DAB2 overexpression treatment.
Patients with diabetic ketosis may suffer from glomerular and tubular injuries that recover after ketosis control. High concentrations of BOHB downregulate megalin expression by inhibiting the AKT/DAB2/megalin signalling pathway and albumin endocytosis in proximal renal tubules.
糖尿病酮症患者常伴有白蛋白尿。我们之前发现急性高血糖可导致肾毒性损伤。在此，我们探讨了过量的酮体水平是否会引起肾损伤及其潜在的机制。
纳入 56 例无酮症的 2 型糖尿病患者（NDK 组）、81 例有酮症的 2 型糖尿病患者（DK 组）和 38 例健康对照者（NC 组）。在控制糖尿病酮症前后收集临床数据。β-羟丁酸（BOHB）是一种 AKT 激活剂，一种 AKT 抑制剂，或转染人肾近端小管上皮细胞（HK-2 细胞）的 DAB2 质粒。
DK 组的尿白蛋白/肌酐比值（ACR）、转铁蛋白（TF）、免疫球蛋白 G（IgG）、β2-微球蛋白（2-MG）、视黄醇结合蛋白（RBP）、N-乙酰-β-D-氨基葡萄糖苷酶（NAG）和β-半乳糖苷酶（GAL）均高于 NC 组和 NDK 组。DK 组患者尿 TF、IgG、2-MG、RBP、NAG 或 GAL 水平升高的比例也更高。控制酮症后，尿微量白蛋白、TF、IgG、2-MG 和 RBP 显著下降。在 HK-2 细胞中，随着 BOHB 浓度的增加，白蛋白内吞和 megalin 表达减少。与 BOHB 处理相比，AKT 激活剂与 BOHB 联合使用可显著增加 DAB2、megalin 水平和白蛋白内吞作用；而 AKT 抑制剂处理则呈现相反的效果。与 BOHB 处理相比，过表达 DAB2 后 BOHB 与 DAB2 联合使用可显著增加 megalin 表达和白蛋白内吞作用。
糖尿病酮症患者可能患有肾小球和肾小管损伤，这些损伤在控制酮症后可恢复。高浓度的 BOHB 通过抑制 AKT/DAB2/megalin 信号通路和近端肾小管的白蛋白内吞作用下调 megalin 表达。
