Zhang Rong M, Oh Jisu, Wice Burton M, Dusso Adriana, Bernal-Mizrachi Carlos
Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
J Steroid Biochem Mol Biol. 2025 Mar;247:106676. doi: 10.1016/j.jsbmb.2025.106676. Epub 2025 Jan 14.
Targeting optimal glycemic control based on hemoglobin A1c (A1c) values reduces but does not abolish the onset of diabetic kidney disease and its progression to chronic kidney disease (CKD). This suggests that factors other than the average glucose contribute to the residual risk. Vitamin D deficiency and frequent episodes of acute hyperglycemia (AH) are associated with the onset of albuminuria and CKD progression in diabetes. This study aimed to determine if moderate levels of AH harm podocytes directly or promote a pro-inflammatory monocyte/macrophage phenotype that leads to podocyte apoptosis, and whether vitamin D deficiency accelerates these processes. We found that AH (16.7 mM D- glucose) didn't induce podocyte apoptosis directly, but it did promote a pro-inflammatory response in human monocytes and macrophages, resulting in an increased TNF-α secretion causing podocyte apoptosis. The AH-induced monocyte TNF-α secretion was inversely correlated with healthy donors' serum 25(OH)D levels. AH induced monocyte TNF-α release by increasing oxidative and ER stress, which in turn increased ADAM17 (A Disintegrin And Metalloprotease 17) and iRhom2 (inactive Rhomboid protein 2) expression, both essential for TNF-α secretion. Additionally, monocyte activation of glucagon-like peptide-1 receptor (GLP-1R), using a GLP-1R agonist, downregulated ADAM17/iRhom2 expression, decreasing TNF-α release and reducing podocyte apoptosis. These results show that a normal vitamin D status may attenuate a mechanism by which AH contributes to podocyte apoptosis and CKD progression and might enhance a novel anti-inflammatory role of GLP-1 to prevent AH-driven CKD progression in diabetes.
基于糖化血红蛋白（A1c）值实现最佳血糖控制可减少但不能消除糖尿病肾病的发生及其向慢性肾脏病（CKD）的进展。这表明除平均血糖外的其他因素也会导致残余风险。维生素D缺乏和频繁的急性高血糖（AH）发作与糖尿病患者蛋白尿的发生和CKD进展有关。本研究旨在确定中度水平的AH是直接损害足细胞，还是促进导致足细胞凋亡的促炎单核细胞/巨噬细胞表型，以及维生素D缺乏是否会加速这些过程。我们发现，AH（16.7 mM D-葡萄糖）不会直接诱导足细胞凋亡，但它确实会促进人类单核细胞和巨噬细胞的促炎反应，导致肿瘤坏死因子-α（TNF-α）分泌增加，从而引起足细胞凋亡。AH诱导的单核细胞TNF-α分泌与健康供体的血清25(OH)D水平呈负相关。AH通过增加氧化应激和内质网应激诱导单核细胞TNF-α释放，进而增加TNF-α分泌所必需的解聚素和金属蛋白酶17（ADAM17）及无活性菱形蛋白2（iRhom2）的表达。此外，使用胰高血糖素样肽-1受体（GLP-1R）激动剂激活单核细胞的GLP-1R，可下调ADAM17/iRhom2表达，减少TNF-α释放并降低足细胞凋亡。这些结果表明，正常的维生素D状态可能会减弱AH导致足细胞凋亡和CKD进展的一种机制，并且可能增强GLP-1的新型抗炎作用，以预防糖尿病中AH驱动的CKD进展。
