Thyroid stimulating hormone aggravates diabetic retinopathy through the mitochondrial apoptotic pathway

Abstract

Diabetic retinopathy (DR) is a common complication of diabetes mellitus. High glucose‐induced mitochondrial apoptosis is involved in the loss of retinal pericytes (PCs), which is considered to be a predominant pathologic change of diabetic retinopathy (DR). A high thyroid stimulating hormone (TSH) serum level is associated with an increased prevalence of DR in diabetic patients. Here, we investigated whether TSH regulated glucose‐induced PCs loss through TSH‐receptor (TSHR)‐dependent mitochondrial apoptosis. First, the serum TSH level was found to be an independent risk factor for DR in Type 2 diabetic study participants (odds ratio = 2.294; 95% confidence interval: 1.925–2.733; p ≤ 0.001). Second, human PCs were treated with different concentrations of glucose, with or without bovine TSH (b‐TSH). Glucose induced mitochondrial apoptosis through various mechanisms, including through regulating the expression of apoptosis‐related proteins and inducing mitochondrial dysfunction, which could be deteriorated by costimulation of glucose and b‐TSH. Additionally, we detected functional TSHR in PCs; blocking TSHR significantly restricted TSH‐induced apoptosis. Thus, the presence of functional TSHR in human retinal PCs may facilitate the effect of high TSH on high glucose‐induced PCs loss through TSHR‐dependent mitochondrial apoptosis.

Diabetic retinopathy: Involved cells, biomarkers, and treatments

“…For example, hyperglycemia-induced ER stress may lead to apoptosis and pericytes loss ( Lai et al, 2017 ). High levels of thyroid stimulating hormone may facilitate the effect of high glucose-induced pericyte loss through thyroid stimulating hormone -receptor -dependent mitochondrial apoptosis in retinal pericytes ( Lin et al, 2021 ). DNA methyltransferase-1 can prevent the overexpression of peroxisome proliferator-activated receptor α by mediating its methylation to increase apoptotic cells and ROS in pericytes ( Zhu Y. et al, 2021 ).…”

“…The metabolic disturbances induced by DR are mainly related to metabolism of glycolysis, polyols, tricarboxylic acid, amino acids, the urea cycle, and lipids ( Xuan et al, 2020 ). Several observational studies have shown that dyslipidemia, mitochondrial apoptosis, and oxidative stress may be the predominant pathological changes of DR ( Miller et al, 2020 ; Fort et al, 2021 ; Lin et al, 2021 ; Rao et al, 2021 ). Vascular endothelial growth factor (VEGF), HbA1c, low-density lipoprotein cholesterol, myeloperoxidase, and advanced glycation end products (AGEs) are pathogenic factors of DR.…”

Correlation Between Thyroid-Related Hormones and Diabetic Retinopathy in Type 2 Diabetes Mellitus Patients with Normal Thyroid Function: A Retrospective Study

“…Abnormally high TSH expression can accelerate oxidative stress, induce vascular endothelial cell damage, and alter local hemodynamics in T2DM patients. 17 These pathological changes can aggravate damage to endothelial cells in the fundus, thicken the basement membrane, and block capillaries, thereby causing visual impairment in T2DM patients. A cross-sectional study found that high TSH levels are an independent risk factor for diabetic macular edema in T2DM patients.…”

Association of thyroid stimulating hormone and time in range with risk of diabetic retinopathy in euthyroid type 2 diabetes

“…The potential mechanism underlying the effects of TSH on the development of DR has been investigated in several studies. Lin et al 30 . detected functional TSH receptors in retinal pericytes, which may facilitate the effect of high TSH on high glucose‐induced PC loss through TSH‐receptor‐dependent mitochondrial apoptosis.…”

“…The potential mechanism underlying the effects of TSH on the development of DR has been investigated in several studies. Lin et al 30 detected functional TSH receptors in retinal pericytes, which may facilitate the effect of high TSH on high glucose-induced PC loss through TSH-receptor-dependent mitochondrial apoptosis. Furthermore, high TSH levels have been reported to be associated with early retinal changes, including retinal arteriolar narrowing 31 and opsin expression changes.…”