Huang Yuhong, Zeng Miao, Yang Mengxue, Zheng Xiaodi, Jin Lulu, Zhang Rui, Wu Yueyue, Li Fei, Yang Bo, Liu Jun
Department of Endocrinology, Shanghai Fifth People's Hospital Affiliated to Fudan University, Shanghai, China.
Fudan University Community Health Research Center (To Be Established), Shanghai, China.
J Diabetes. 2025 Jul;17(7):e70125. doi: 10.1111/1753-0407.70125.
Renal HMGCS2 upregulation is associated with lipid deposition. However, the expression pattern and role of Hmgcs2 in the perirenal adipose tissue (PRAT) is not clear. This study was designed to elucidate the contribution of Hmgcs2 in the pathogenesis of obese diabetic kidney disease mice.
12-week-old db/db (diabetic) and db/m (control) mice were fed high-fat or normal diets, respectively. At 12, 16, and 20 weeks, mice (n = 4/group/timepoint) were euthanized for metabolic profiling (body weight, blood glucose, urinary ACR) and tissue collection (kidney, PRAT). Tissues were analyzed for TNF-α mRNA (qPCR), HMGCS2 expression (IHC/WB/IF), lipid deposition (Oil Red O), and histopathology (HE staining). PRAT triglycerides (colorimetric assay) and lipidomics (UPLC-MS/MS) were assessed. HMGCS2-knockout mice (CRISPR-generated) underwent metabolic tests (OGTT/ITT) before terminal tissue analysis.
(1) Compared with db/mPRAT, db/db PRAT had significantly enlarged adipocytes and increased TG content. The expression of HMGCS2 in renal and PRAT was significantly greater in db/db mice. (2) Hmgcs2 was equally expressed in db/db renal and PRAT. PRAT expansion increases the inflammatory factor TNF-α, which occurs earlier in PRAT than in renal tissue.(3) Genetic ablation of HMGCS2 in mice significantly decreased renal and PRAT TG accumulation, concomitant with attenuated inflammation. (4) LC-MS/MS analysis revealed that TGs are the main PRAT lipid component. Db/db PRAT TG content was significantly greater than that in db/m. Db/db proximal PRAT TG content is greater than that of the distal region, with seven upregulated TG lipid molecules (TG (38:3)+NH4, TG (50:5)+NH4, TG (52:12e)+Na, TG (56:9e)+H, TG (57:6e)+H, FA (18:1)+H, and ST (m45:3)+NH4), among which TG (38:3) has the highest expression.
Our study strongly suggests that lipids, especially TGs, are deposited in the kidneys and PRAT of DKD mice, with proximal-distal PRAT differences. HMGCS2 may be involved in kidneys and PRAT TG deposition. PRAT-lipid-metabolism-induced inflammation may occur before blood-glucose-related kidney damage.
肾脏中HMGCS2的上调与脂质沉积有关。然而，Hmgcs2在肾周脂肪组织（PRAT）中的表达模式和作用尚不清楚。本研究旨在阐明Hmgcs2在肥胖糖尿病肾病小鼠发病机制中的作用。
将12周龄的db/db（糖尿病）小鼠和db/m（对照）小鼠分别喂以高脂或正常饮食。在12、16和20周时，对小鼠（每组/每个时间点n = 4）实施安乐死，以进行代谢分析（体重、血糖、尿ACR）和组织采集（肾脏、PRAT）。对组织进行TNF-α mRNA分析（qPCR）、HMGCS2表达分析（免疫组化/蛋白质免疫印迹/免疫荧光）、脂质沉积分析（油红O染色）和组织病理学分析（苏木精-伊红染色）。评估PRAT甘油三酯（比色法）和脂质组学（超高效液相色谱-串联质谱）。在进行终末组织分析之前，对HMGCS2基因敲除小鼠（通过CRISPR技术构建）进行代谢测试（口服葡萄糖耐量试验/胰岛素耐量试验）。
（1）与db/m PRAT相比，db/db PRAT的脂肪细胞显著增大，TG含量增加。db/db小鼠肾脏和PRAT中HMGCS2的表达显著更高。（2）Hmgcs2在db/db小鼠的肾脏和PRAT中表达水平相当。PRAT的扩张增加了炎性因子TNF-α，这在PRAT中比在肾组织中更早发生。（3）小鼠中HMGCS2的基因缺失显著降低了肾脏和PRAT中TG的积累，同时炎症减轻。（4）液相色谱-串联质谱分析显示，甘油三酯是PRAT的主要脂质成分。db/db PRAT的TG含量显著高于db/m。db/db近端PRAT的TG含量高于远端区域，有7种上调的TG脂质分子（TG (38:3)+NH4, TG (50:5)+NH4, TG (52:12e)+Na, TG (56:9e)+H, TG (57:6e)+H, FA (18:1)+H, 和ST (m45:3)+NH4），其中TG (38:3)表达最高。
我们的研究强烈表明，脂质，尤其是甘油三酯，沉积在DKD小鼠的肾脏和PRAT中，PRAT存在近端-远端差异。HMGCS2可能参与肾脏和PRAT中TG的沉积。PRAT脂质代谢诱导的炎症可能在与血糖相关的肾脏损伤之前发生。
