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Published on: June 13, 2025
Effects of PPARs/20-HETE on the renal impairment under diabetic conditions
Shumei Ding1, Jiajun Huang1, Hongmei Qiu1
1Department of Pharmacology, Chongqing Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing Medical University, Chongqing, 400016, China.
Abstract:
Diabetic nephropathy (DN) is one of the most severe complications of diabetes mellitus. The pathomolecular events behind DN remain uncertain. Peroxisome proliferator-activated receptors (PPARs) play essential functions in the development of DN. Meanwhile, 20-hydroxyeicosatetraenoic acid (20-HETE) also plays central roles in the regulation of renal function. However, the relationship between PPARs and 20-HETE is rarely studied in DN. It was revealed in our study that both PPARs expression and CYP4A-20-HETE level were decreased under DN conditions in vivo and in vitro. Supplementation with bezafibrate, a PPAR pan-agonist, improved the damage of kidney in DN mice and in high glucose-induced NRK-52E cells, following the up-regulation of PPARs and the increase of CYP4A-20-HETE. PPARα antagonist (MK886), PPARβ antagonist (GSK0660), and PPARγ antagonist (GW9662) reversed the protection of bezafibrate in NRK-52E, and abrogated the up-regulation of CYP4A-20-HETE produced by bezafibrate. Noteworthily, 20-HETE synthetase inhibitor, HET0016, also blocked the bezafibrate-mediated improvement of NRK-52E, and abolished the up-regulation of PPARs expression. Collectively, our data suggest that the concurrent down-regulation and interaction of PPARs and 20-HETE play crucial roles in the pathogenesis process of DN, and we provide a novel evidence that PPARs/20-HETE signaling may be served as a therapeutic target for DN patients.
Insights
Diabetic nephropathy involves decreased PPARs and 20-HETE. Bezafibrate treatment improved kidney damage by up-regulating these factors, suggesting PPARs/20-HETE signaling as a potential therapeutic target.
Area of Science:
- Nephrology
- Endocrinology
- Molecular Biology
Background:
- Diabetic nephropathy (DN) is a severe diabetes complication with uncertain pathomolecular mechanisms.
- Peroxisome proliferator-activated receptors (PPARs) and 20-hydroxyeicosatetraenoic acid (20-HETE) are implicated in DN pathogenesis and renal function regulation.
- The interplay between PPARs and 20-HETE in DN remains underexplored.
Purpose of the Study:
- To investigate the relationship between PPARs and 20-HETE in diabetic nephropathy.
- To explore the therapeutic potential of targeting the PPARs/20-HETE signaling pathway in DN.
Main Methods:
- Assessed PPARs expression and CYP4A-20-HETE levels in DN models (in vivo and in vitro).
- Administered bezafibrate (PPAR pan-agonist) to DN mice and high glucose-induced NRK-52E cells.
- Utilized PPAR antagonists (MK886, GSK0660, GW9662) and a 20-HETE synthetase inhibitor (HET0016) to probe signaling pathways.
Main Results:
- DN conditions led to decreased PPARs expression and CYP4A-20-HETE levels.
- Bezafibrate treatment ameliorated kidney damage, up-regulating PPARs and increasing CYP4A-20-HETE.
- PPAR antagonists and HET0016 reversed bezafibrate's protective effects and modulated PPARs/20-HETE levels, indicating their interaction.
Conclusions:
- Concurrent down-regulation of PPARs and 20-HETE plays a critical role in DN pathogenesis.
- The PPARs/20-HETE signaling pathway represents a novel therapeutic target for diabetic nephropathy.
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