Department of Endocrinology, Renmin Hospital of Wuhan University, Wuhan, 430060, China.
Department of Nephrology, Renmin Hospital of Wuhan University, Wuhan, 430060, China.
Eur J Pharmacol. 2024 Nov 15;983:176905. doi: 10.1016/j.ejphar.2024.176905. Epub 2024 Aug 21.
The gut microbiome-metabolites-kidney axis is a potential target for treating diabetic kidney disease (DKD). Our previous study found that Liraglutide attenuated DKD in rats by decreasing renal tubular ectopic lipid deposition (ELD) and serum metabolites levels, including L-5-Oxoproline (5-OP). However, the response of gut microbiome-metabolites-kidney axis to Liraglutide in DKD rats and the effect of 5-OP on ELD remain unknown. In this study, Sprague-Dawley rats were used as an animal model of DKD. They were subjected to a high fat diet, streptozotocin and uninephrectomy, followed by Liraglutide treatment (0.4 mg/kg d). Additionally, HK-2 cells were incubated with 30 mM glucose and 200 μM palmitate for 24h, and exposed to different concentrations of 5-OP. In DKD rats, Liraglutide dramatically improved the renal tubule structure. It increased the Simpson index (F = 4.487, p = 0.035) and reduced the Actinobacteria-to-Bacteroidetes ratio (F = 6.189, p = 0.014). At the genus level, Liraglutide increased the relative abundance of Clostridium, Oscillospira, Sarcina, SMB53, and 02d06 while decreasing that of Allobaculum. Meanwhile, 13 metabolites were significantly altered after Liraglutide treatment. Multi-omics analysis found that 5-OP levels were positively correlated with Clostridium abundance but negatively correlated with renal injury related indicators. In HK-2 cells, 5-OP significantly reduced the ELD in a dose-dependent manner through inhibiting the expression of SREBP1 and FAS. Overall, the renoprotective effect of Liraglutide in DKD rats is linked to the improvement of the gut microbiota composition and increased serum 5-OP levels, which may reduce ELD in renal tubular cells by lowering lipid synthesis.
肠菌-代谢物-肾脏轴是治疗糖尿病肾病（DKD）的潜在靶点。我们之前的研究发现，利拉鲁肽通过减少肾小管异位脂质沉积（ELD）和血清代谢物水平，包括 L-5-氧脯氨酸（5-OP），来减轻 DKD 大鼠的病情。然而，DKD 大鼠肠菌-代谢物-肾脏轴对利拉鲁肽的反应以及 5-OP 对 ELD 的影响尚不清楚。在这项研究中，SD 大鼠被用作 DKD 的动物模型。它们接受高脂肪饮食、链脲佐菌素和单侧肾切除术，随后接受利拉鲁肽治疗（0.4mg/kg/d）。此外，HK-2 细胞在 30mM 葡萄糖和 200μM 棕榈酸孵育 24 小时后，暴露于不同浓度的 5-OP 中。在 DKD 大鼠中，利拉鲁肽显著改善了肾小管结构。它增加了 Simpson 指数（F=4.487，p=0.035），降低了放线菌与拟杆菌的比例（F=6.189，p=0.014）。在属水平上，利拉鲁肽增加了梭菌、颤螺旋菌、明串珠菌、SMB53 和 02d06 的相对丰度，同时降低了 Allobaculum 的相对丰度。同时，利拉鲁肽治疗后有 13 种代谢物显著改变。多组学分析发现，5-OP 水平与梭菌丰度呈正相关，与肾损伤相关指标呈负相关。在 HK-2 细胞中，5-OP 通过抑制 SREBP1 和 FAS 的表达，以剂量依赖的方式显著减少 ELD。总体而言，利拉鲁肽在 DKD 大鼠中的肾保护作用与改善肠道微生物组成和增加血清 5-OP 水平有关，这可能通过降低脂质合成来减少肾小管细胞中的 ELD。
