Zhou Hua, Mu Xiaodie, Hu Huiyue, Zhao Shuya, Hu Nan, Yang Min, Jiang Jingting
Department of Nephrology, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, People's Republic of China.
Department of Nephrology, The Second People's Hospital of Hefei, Hefei, 230011, People's Republic of China.
Drug Des Devel Ther. 2025 Jul 29;19:6469-6485. doi: 10.2147/DDDT.S530823. eCollection 2025.
Diabetic kidney disease (DKD) is a major contributor to chronic kidney disease worldwide. Bile acids (BAs) are increasingly recognized as key regulators of glucose metabolism and kidney function. This study aimed to investigate the role of BA metabolism in the progression of DKD.
Plasma BA profiles were measured in healthy controls (HC), patients with type 2 diabetes mellitus (T2DM), and patients with DKD using ultra-high-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). After identifying potential BA biomarkers in the clinical cohort, in vivo validation was conducted using dehydrolithocholic acid (DHLCA) intervention in DKD mouse model. Kidney injury markers, as well as the expression of Takeda G protein-coupled receptor 5 (TGR5) and farnesoid X receptor (FXR), were evaluated. In addition, gut microbiota (GM) composition was analyzed via metagenomic sequencing following DHLCA treatment.
The plasma DHLCA levels were significantly lower in DKD with macroalbuminuria group compared to T2DM group and DKD with microalbuminuria group ( < 0.01). Partial Spearman correlation analysis adjusted for age and diabetes duration showed that DHLCA levels were negatively correlated with urine albumin ( = -0.347; 95% CI, -0.531 to -0.135; q = 0.008) and urine albumin-to-creatinine ratio (UACR) ( = -0.332; 95% CI, -0.499 to -0.155; q = 0.010). In vivo, DHLCA administration significantly reduced UACR and fasting blood glucose (FBG) levels ( < 0.01), and improved liver function (ALT, < 0.05) in DKD mice. DHLCA treatment attenuated renal tubular injury, restored TGR5 and FXR expression in kidney tissue, and decreased levels of kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL). Metagenomic analysis revealed an enrichment of following DHLCA treatment.
DHLCA may represent a promising therapeutic candidate for DKD by targeting the TGR5/FXR signaling pathway and GM remodeling. Its metabolic and kidney benefits, along with an improved hepatic profile and absence of hepatotoxicity, support further translational investigation.
糖尿病肾病（DKD）是全球慢性肾脏病的主要病因。胆汁酸（BAs）越来越被认为是葡萄糖代谢和肾功能的关键调节因子。本研究旨在探讨胆汁酸代谢在DKD进展中的作用。
采用超高效液相色谱-串联质谱法（UPLC-MS/MS）检测健康对照（HC）、2型糖尿病（T2DM）患者和DKD患者的血浆胆汁酸谱。在临床队列中确定潜在的胆汁酸生物标志物后，在DKD小鼠模型中使用脱氢石胆酸（DHLCA）干预进行体内验证。评估肾损伤标志物以及武田G蛋白偶联受体5（TGR5）和法尼酯X受体（FXR）的表达。此外，在DHLCA治疗后通过宏基因组测序分析肠道微生物群（GM）组成。
与T2DM组和微量白蛋白尿DKD组相比，大量白蛋白尿DKD组的血浆DHLCA水平显著降低（<0.01）。经年龄和糖尿病病程校正的偏Spearman相关性分析显示，DHLCA水平与尿白蛋白（=-0.347；95%CI，-0.531至-0.135；q=0.008）和尿白蛋白/肌酐比值（UACR）（=-0.332；95%CI，-0.499至-0.155；q=0.010）呈负相关。在体内，给予DHLCA可显著降低DKD小鼠的UACR和空腹血糖（FBG）水平（<0.01），并改善肝功能（ALT，<0.05）。DHLCA治疗减轻了肾小管损伤，恢复了肾组织中TGR5和FXR的表达，并降低了肾损伤分子-1（KIM-1）和中性粒细胞明胶酶相关脂质运载蛋白（NGAL）的水平。宏基因组分析显示DHLCA治疗后 富集。
DHLCA可能通过靶向TGR5/FXR信号通路和肠道微生物群重塑成为DKD的一种有前景的治疗候选物。其代谢和肾脏益处，以及改善的肝脏状况和无肝毒性，支持进一步的转化研究。
