Department of Endocrinology and Metabolism, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, China.
Sichuan Clinical Research Center for Nephropathy, Luzhou, Sichuan 646000, China.
Oxid Med Cell Longev. 2022 Apr 19;2022:7177889. doi: 10.1155/2022/7177889. eCollection 2022.
Chronic hyperglycemia-induced inflammation is recognized as the most important pathophysiological process in diabetic kidney disease (DKD). As maresin 1 (MaR1) is an extensive anti-inflammatory lipid mediator, the present study investigated the protective role of MaR1 in the pathogenesis of DKD and its clinical relevance.
Serum MaR1 concentrations were analyzed in 104 subjects with normal glucose tolerant, type 2 diabetes (T2DM), or DKD. Streptozotocin (STZ) together with high fat diet was used to induce male C57BL/6 J mice into diabetic mice which were treated with MaR1. Human renal tubule epithelial cells (HK-2 cells) were treated by high glucose for glucotoxicity cell model and transfected with LGR6 siRNA for knockdown with MaR1 added，and detected oxidative stress and inflammatory related factors.
Serum MaR1 concentrations were significant decreased in T2DM with or without kidney disease compared with normal participant and were lowest in patients with DKD. Serum MaR1 concentrations were negatively correlated with hemoglobin A1c (HbA1c), duration of diabetes, urinary albumin to creatinine ratio (UACR), neutrophil, and neutrophil-lymphocyte ratio and were positively correlated with high-density lipoprotein-cholesterol (HDL-C) and estimated glomerular filtration rate (eGFR). In mouse model, MaR1 injection alleviated hyperglycemia, UACR and the pathological progression of DKD. Interestingly, the renal expression of LGR6 was down-regulated in DKD and high glucose treated HK-2 cells but up-regulated by MaR1 treatment. Mechanistically, MaR1 alleviated inflammation via LGR6-mediated cAMP-SOD2 antioxidant pathway in DKD mice and high glucose treated HK-2 cells.
Our study demonstrates that decreased serum MaR1 levels were correlated with the development of DKD. MaR1 could alleviate DKD and glucotoxicity-induced inflammation via LGR6-mediated cAMP-SOD2 antioxidant pathway. Thus, our present findings identify MaR1 as a predictor and a potential therapeutic target for DKD.
慢性高血糖诱导的炎症被认为是糖尿病肾病（DKD）最重要的病理生理过程。由于maresin 1（MaR1）是一种广泛的抗炎脂质介质，本研究探讨了 MaR1 在 DKD发病机制中的保护作用及其临床相关性。
分析了 104 例糖耐量正常、2 型糖尿病（T2DM）和 DKD 患者的血清 MaR1 浓度。链脲佐菌素（STZ）联合高脂饮食诱导雄性 C57BL/6J 小鼠发生糖尿病，并用 MaR1 治疗。将人肾小管上皮细胞（HK-2 细胞）用高糖处理以建立糖毒性细胞模型，并转染 LGR6 siRNA 以敲低 MaR1 处理，检测氧化应激和炎症相关因子。
与正常参与者相比，T2DM 合并或不合并肾病患者的血清 MaR1 浓度显著降低，DKD 患者最低。血清 MaR1 浓度与血红蛋白 A1c（HbA1c）、糖尿病病程、尿白蛋白与肌酐比值（UACR）、中性粒细胞和中性粒细胞与淋巴细胞比值呈负相关，与高密度脂蛋白胆固醇（HDL-C）和估计肾小球滤过率（eGFR）呈正相关。在小鼠模型中，MaR1 注射可减轻高血糖、UACR 和 DKD 的病理进展。有趣的是，在 DKD 和高糖处理的 HK-2 细胞中，肾脏 LGR6 的表达下调，但 MaR1 处理后上调。机制上，MaR1 通过 LGR6 介导的 cAMP-SOD2 抗氧化途径减轻 DKD 小鼠和高糖处理的 HK-2 细胞中的炎症。
我们的研究表明，血清 MaR1 水平降低与 DKD 的发生有关。MaR1 可通过 LGR6 介导的 cAMP-SOD2 抗氧化途径减轻 DKD 和高糖诱导的炎症。因此，我们的研究结果表明 MaR1 可作为 DKD 的预测因子和潜在治疗靶点。
