Division of Genetics and Metabolism, Children's Hospital of China Medical University, Taichung 40402, Taiwan.
School of Medicine, China Medical University, Taichung 40402, Taiwan.
J Clin Endocrinol Metab. 2022 Aug 18;107(9):2556-2570. doi: 10.1210/clinem/dgac378.
Nephropathy is a severe complication of type 1 diabetes (T1DM). However, the interaction between the PDHA1-regulated mechanism and CD4+ T cells in the early stage of kidney tubular injury remains unknown.
To evaluate the role of PDHA1 in the regulation of tubular cells and CD4+ T cells and further to study its interaction in tubular cell injury in T1DM.
Plasma and total RNA were collected from T cells of T1DM patients (n = 35) and healthy donors (n = 33) and evaluated for neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1, PDHA1, and biomarkers of CD4+ T cells including T helper 1 cells (Th1) and regulatory T cells (Treg) markers. HK-2 cells cocultured with CD4+ T cells from T1DM patients or healthy donors (HDs) to evaluate the interaction with CD4+ T cells.
Increased PDHA1 gene expression levels in CD4+ T cells were positively associated with the plasma level of NGAL in T1DM patients and HDs. Our data demonstrated that the Th1/Treg subsets skewed Th1 in T1DM. Knockdown of PDHA1 in kidney tubular cells decreased ATP/ROS production, NAD/NADH ratio, mitochondrial respiration, and cell apoptosis. Furthermore, PDHA1 depletion induced impaired autophagic flux. Coculture of tubular cells and T1DM T cells showed impaired CPT1A, upregulated FASN, and induced kidney injury.
Our findings indicate that Th1 cells induced tubular cell injury through dysregulated metabolic reprogramming and autophagy, thereby indicating a new therapeutic approach for kidney tubular injury in T1DM.
肾病是 1 型糖尿病（T1DM）的严重并发症。然而，PDHA1 调节机制与早期肾小管损伤中的 CD4+T 细胞之间的相互作用尚不清楚。
评估 PDHA1 在肾小管细胞和 CD4+T 细胞调节中的作用，并进一步研究其在 T1DM 肾小管细胞损伤中的相互作用。
收集 T1DM 患者（n=35）和健康供体（n=33）的 T 细胞的血浆和总 RNA，评估中性粒细胞明胶酶相关脂质运载蛋白（NGAL）、肾损伤分子 1、PDHA1 以及 CD4+T 细胞的生物标志物，包括 Th1 细胞和调节性 T 细胞（Treg）标志物。HK-2 细胞与 T1DM 患者或健康供体（HDs）的 CD4+T 细胞共培养，以评估与 CD4+T 细胞的相互作用。
CD4+T 细胞中 PDHA1 基因表达水平的增加与 T1DM 患者和 HDs 中血浆 NGAL 水平呈正相关。我们的数据表明，T1DM 中 Th1/Treg 亚群向 Th1 倾斜。在肾小管细胞中敲低 PDHA1 可降低 ATP/ROS 产生、NAD/NADH 比值、线粒体呼吸和细胞凋亡。此外，PDHA1 耗竭可诱导自噬通量受损。肾小管细胞和 T1DM T 细胞共培养可导致 CPT1A 减少、FASN 上调，并诱导肾脏损伤。
我们的研究结果表明，Th1 细胞通过失调的代谢重编程和自噬诱导肾小管细胞损伤，从而为 T1DM 肾小管损伤提供了一种新的治疗方法。
