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Pharmacological Modulation of ALDH2-SIRT1-Endoplasmic Reticulum Stress Axis in MNU-Induced Retinal Degeneration in
Wenhui Lan1, Qiurui He2, Caifeng Cao1
1Fuzong Clinical Medical College of Fujian Medical University, Dongfang Hospital Affiliated to Xiamen University.
Abstract:
This study investigated the protective effects of aldehyde dehydrogenase 2 (ALDH2) activation (via Alda-1), ALDH2 inhibition (via Daidzin), and the modulation of sirtuin 1 (SIRT1) and endoplasmic reticulum stress (ERS) on methyl-nitrosourea (MNU)-induced retinal damage in C57BL/6 mice. Seventy-two mice were randomly assigned to eight groups, including a control group, a MNU-alone group, and various treatment combination groups. Mice were administered with intraperitoneal injections of agonists and inhibitors targeting the ALDH2-SIRT1-ERS axis, respectively. Body weight, retinal layer thickness, and aldehyde metabolism biomarkers were assessed on the second and fourth day post-treatment. MNU administration induced retinal degeneration, resulting in significant body weight loss in all groups except the control. Treatment with Alda-1 attenuated retinal damage, while Daidzin exacerbated it. Pharmacological inhibition of SIRT1 (via EX-527) diminished the protective effects of Alda-1, and ERS induction (via TUN) nearly abolished its benefits. Conversely, SIRT1 activation (via SRT1720) mitigated the adverse effects of Daidzin, while ERS inhibition (via 4-PBA) partially alleviated Daidzin's impact. Furthermore, MNU increased levels of aldehyde metabolism markers (malondialdehyde [MDA] and 4-hydroxy-2-nonenal [4-HNE]), with Alda-1 reducing and Daidzin elevating these levels. Besides, pharmacological modulation of the SIRT1/ERS pathways intervened in the regulatory effects of Alda-1 and Daidzin on the aldehyde metabolism. Overall, ALDH2 activation protected retinal structure and regulated aldehyde metabolism, highlighting the critical role of the ALDH2-SIRT1/ERS signaling axis in mitigating retinal degeneration.
Insights
Aldehyde dehydrogenase 2 (ALDH2) activation protects against retinal damage by regulating aldehyde metabolism. This highlights the ALDH2-SIRT1/ERS pathway
Area of Science:
- Ophthalmology
- Biochemistry
- Pharmacology
Background:
- Methyl-nitrosourea (MNU) induces retinal degeneration.
- Aldehyde dehydrogenase 2 (ALDH2) plays a role in aldehyde metabolism and cellular protection.
- Sirtuin 1 (SIRT1) and endoplasmic reticulum stress (ERS) are implicated in cellular damage pathways.
Purpose of the Study:
- To investigate the protective effects of ALDH2 activation and inhibition on MNU-induced retinal damage.
- To explore the roles of SIRT1 and ERS modulation in the context of ALDH2 activity and retinal injury.
- To elucidate the ALDH2-SIRT1-ERS signaling axis in mitigating retinal degeneration.
Main Methods:
- C57BL/6 mice were subjected to MNU-induced retinal damage.
- Mice were treated with ALDH2 activator (Alda-1), inhibitor (Daidzin), and modulators of SIRT1 and ERS.
- Evaluated body weight, retinal layer thickness, and aldehyde metabolism biomarkers (MDA, 4-HNE).
Main Results:
- MNU induced significant retinal degeneration and body weight loss.
- Alda-1 treatment attenuated retinal damage and reduced aldehyde markers; Daidzin exacerbated damage and increased markers.
- SIRT1 inhibition or ERS induction diminished Alda-1's protective effects, while SIRT1 activation or ERS inhibition modulated Daidzin's effects.
Conclusions:
- ALDH2 activation, specifically via Alda-1, demonstrates significant protective effects against MNU-induced retinal damage.
- The ALDH2-SIRT1-ERS signaling axis is critical in regulating aldehyde metabolism and protecting retinal structure.
- Targeting ALDH2 offers a potential therapeutic strategy for retinal degeneration.