Journal Article Ppublish
PubMed: 40708536 DOI: 10.1111/1753-0407.70125
Analysis of HMGCS2 Expression and TG Lipidomics in the Perirenal Adipose Tissue of Obese Diabetic Nephropathy Mice.
J Diabetes 17(7):e70125
Authors: Yuhong Huang, Miao Zeng, Mengxue Yang, Xiaodi Zheng, Lulu Jin, Rui Zhang, Yueyue Wu, Fei Li, Bo Yang, Jun Liu
Affiliations
- 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.
- Department of Endocrinology, Shanghai Fifth People's Hospital Affiliated to Fudan University, Shanghai, China. Department of Infectious Diseases, Shanghai Fifth People's Hospital Affiliated to Fudan University, Shanghai, China.
- 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. Department of Endocrinology, Shanghai Pudong New Area People's Hospital, Shanghai, China.
- Department of Endocrinology, Affiliated Hospital of Zunyi Medical University, Zunyi, China.
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.
MeSH
Diabetes Mellitus, Blood, Diabetic Nephropathies, Kidney, Tissues, Lipidomics, Adipose Tissue