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Activation of PPARγ Attenuates Age-Related Lacrimal Gland Dysfunction by Alleviating Endoplasmic Reticulum
Han Zhao1,2, Yiming Xu1,2, Peiwen Feng1,2
1Department of Ophthalmology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, People's Republic of China.
Purpose:
The potential mechanism underlying age-related lacrimal gland alterations remains unclear. Herein, we aimed to investigate the regulatory role of endoplasmic reticulum stress (ERS) and ferroptosis in the lacrimal glands of aging male C57BL/6J mice.
Methods:
Two- and 12-month-old male C57BL/6J mice were used in this study. The mice received an ERS inducer (tunicamycin), ERS inhibitor (4-phenylbutyric acid), a protein kinase R-like endoplasmic reticulum-resident kinase (PERK) inhibitor (GSK2606414), the ferroptosis inhibitors ferrostatin-1 (Fer-1), and deferoxamine mesylate (DFOM), or a peroxisome proliferator-activated receptor γ (PPARγ) agonist (rosiglitazone) or antagonist (GW9662). Histological structure, interstitial fibrosis, extraorbital lipid-droplet accumulation, and tear secretion in the lacrimal gland were examined.
Results:
ERS biomarkers and the PERK pathway were upregulated in the aged lacrimal gland tissues. Concomitantly, ferroptosis levels were significantly increased in the lacrimal gland of 12-month-old mice; this finding was characterized by increased lipid peroxidation and oxidative stress and diminished levels of glutathione peroxidase 4, which was regulated by PERK. Furthermore, treatment with the PPARγ agonist rosiglitazone restored tear secretion and reduced PERK-mediated ERS and ferroptosis levels by increasing PPARγ levels in the aged lacrimal gland and alleviating lipid accumulation by enhancing fatty acid oxidation activity, thereby attenuating lipid metabolic disorders within the lacrimal gland of aged mice. However, these effects were reversed by the PPARγ antagonist GW9662.
Conclusions:
Our findings demonstrate that rosiglitazone alleviates age-related lacrimal dysfunction in mice through the PPARγ pathway. Our results offer a novel molecular target and therapeutic approach against age-related lacrimal gland disorders.
