Analysis of HMGCS2 Expression and TG Lipidomics in the Perirenal Adipose Tissue of Obese Diabetic Nephropathy Mice

IF 3 2区医学 Q2 ENDOCRINOLOGY & METABOLISM

Journal of Diabetes Pub Date : 2025-07-25 DOI:10.1111/1753-0407.70125

Yuhong Huang, Miao Zeng, Mengxue Yang, Xiaodi Zheng, Lulu Jin, Rui Zhang, Yueyue Wu, Fei Li, Bo Yang, Jun Liu

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Abstract

Background and Aims

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.

Methods

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.

Results

(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.

Conclusion

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.

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肥胖糖尿病肾病小鼠肾周脂肪组织HMGCS2表达及TG脂质组学分析

背景与目的肾HMGCS2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。方法12周龄db/db（糖尿病小鼠）和db/m（对照组小鼠）分别饲喂高脂饲料和正常饲料。在12、16和20周时，对小鼠（n = 4/组/时间点）实施安乐死，进行代谢分析（体重、血糖、尿ACR）和组织收集（肾脏、PRAT）。组织分析TNF-α mRNA （qPCR）、HMGCS2表达（IHC/WB/IF）、脂质沉积（Oil Red O）和组织病理学（HE染色）。评估PRAT甘油三酯（比色法）和脂质组学（UPLC-MS /MS）。hmgcs2敲除小鼠（crispr生成）在进行终末组织分析之前进行代谢测试（OGTT/ITT）。结果(1)与db/mPRAT相比，db/db PRAT显著增大脂肪细胞，增加TG含量。HMGCS2在肾和PRAT中的表达在db/db小鼠中显著增加。(2) Hmgcs2在db/db肾组织和PRAT组织中表达量相等。PRAT扩张增加炎症因子TNF-α，其在PRAT中比在肾组织中更早发生。(3)小鼠HMGCS2基因消融可显著降低肾脏和PRAT TG积累，并伴有炎症减轻。(4) LC-MS /MS分析显示tg是PRAT的主要脂质成分。Db/ Db PRAT TG含量显著高于Db/ m。近端PRAT区TG含量Db/ Db大于远端，7种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、ST (m45:3)+NH4）表达上调，其中TG（38:3）表达量最高。结论脂质，尤其是tg，在DKD小鼠的肾脏和PRAT中沉积，且PRAT近端和远端存在差异。HMGCS2可能参与肾脏和PRAT的TG沉积。prat -脂质代谢引起的炎症可能发生在血糖相关性肾损害之前。

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来源期刊

Journal of Diabetes ENDOCRINOLOGY & METABOLISM-

CiteScore

6.50

自引率

2.20%

发文量

审稿时长

>12 weeks

期刊介绍： Journal of Diabetes (JDB) devotes itself to diabetes research, therapeutics, and education. It aims to involve researchers and practitioners in a dialogue between East and West via all aspects of epidemiology, etiology, pathogenesis, management, complications and prevention of diabetes, including the molecular, biochemical, and physiological aspects of diabetes. The Editorial team is international with a unique mix of Asian and Western participation. The Editors welcome submissions in form of original research articles, images, novel case reports and correspondence, and will solicit reviews, point-counterpoint, commentaries, editorials, news highlights, and educational content.