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Is PPARG the key gene in diabetic retinopathy?

ABSTRACT: Diabetic retinopathy, a microvascular complication of diabetes mellitus, is major cause of non-inherited blindness among adults. Although diabetic retinopathy is a common complication of diabetes, we still know little about the underlying molecular mechanisms. In recent years, complex connections between important molecules and pathways in the onset and progression of diabetic retinopathy, such as advanced glycation end products, oxidative stress and inflammation, have been elucidated. Biochemical, genetic and functional studies strongly indicate peroxisome proliferator-activated receptor-? (PPAR?), a pleiotropic transcription factor, as a primary target in the treatment of diabetic retinopathy. In this issue, Song et al. detail the role of PPAR? in diabetic retinopathy-related disorders, illustrating PPAR?-mediated inhibition of diabetes-induced leukostasis and leakage, and its beneficial role in modulating inflammation, angiogenesis and apoptosis in retinal and endothelial cells. Moreover, they describe alternative treatments for diabetic retinopathy, such as plant-derived PPAR? ligands, proposing their use - in combination with standard therapies - for modulation of diabetic retinopathy.

SUBMITTER: Costa V

PROVIDER: S-EPMC3252961 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

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Is PPARG the key gene in diabetic retinopathy?

Costa Valerio V Ciccodicola Alfredo A

British journal of pharmacology 20120101 1

Diabetic retinopathy, a microvascular complication of diabetes mellitus, is major cause of non-inherited blindness among adults. Although diabetic retinopathy is a common complication of diabetes, we still know little about the underlying molecular mechanisms. In recent years, complex connections between important molecules and pathways in the onset and progression of diabetic retinopathy, such as advanced glycation end products, oxidative stress and inflammation, have been elucidated. Biochemic ...[more]

PMID: 21501146

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Project description:BackgroundDiabetic retinopathy (DR) is a leading cause of vision loss worldwide. Recent studies highlighted the crucial impact of circadian rhythms (CR) on normal retinopathy in response to the external light cues. However, the role of circadian rhythms in DR pathogenesis and potential investigational drugs remains unclear.MethodsTo investigate the weather CR affects DR, differential expression analysis was employed to identify differentially expressed genes (DEGs) from the GEO database (GSE160306). Functional enrichment analysis was conducted to identify relevant signaling pathways. LASSO regression was utilized to screen pivotal genes. Weighted gene co-expression network anlaysis (WGCNA) was applied to identify different modules. Additionally, we use the Comparative Toxicogenomics Database (CTD) database to search key genes related to drugs or molecular compounds. The diabetic mouse model received three consecutive intraperitoneal injections of streptozotocin (STZ) during 3 successive days.ResultsWe initially identified six key genes associated with circadian rhythm in DR, including COL6A3, IGFBP2, IGHG4, KLHDC7A, RPL26P30, and MYL6P4. Compared to normal tissue, the expression levels of COL6A3 and IGFB2 were significantly increased in DR model. Furthermore, we identified several signaling pathways, including death domain binding, insulin-like growth factor I binding, and proteasome binding. We also observed that COL6A3 was positively correlated with macrophages (cor=0.628296895, p=9.96E-08) and Th17 cells (cor=0.665120835, p=9.14E-09), while IGFBP2 showed a negatively correlated with Tgd (cor=-0.459953045, p=0.000247284) and Th2 cells (cor=-0.442269719, p=0.000452875). Finally, we identified four drugs associated with key genes: Resveratrol, Vitamin E, Streptozocin, and Sulindac.ConclusionOur findings revealed several key genes related to circadian rhythms and several relevant drugs in DR, providing a novel insight into the mechanism of DR and potential implications for future DR treatment. This study contributes to a better understanding of CR in DR and its implications for future therapeutic interventions.

Project description:The aim of this study was to investigate the association of three single nucleotide polymorphisms in the erythropoietin gene polymorphisms with diabetic retinopathy and additional role of gene-gene interaction on diabetic retinopathy risk. A total of 1193 patients (579 men, 614 women) with type 2 diabetes mellitus were selected, including 397 diabetic retinopathy patients and 796 controls (type 2 diabetes mellitus patients without diabetic retinopathy); the mean age of all participants was 56.7 ± 13.9 years. Three single nucleotide polymorphisms were selected: rs507392, rs1617640, and rs551238. The t-test was used for comparison of erythropoietin protein level erythropoietin levels in patients having different erythropoietin genotypes. Logistic regression model was used to examine the association between three single nucleotide polymorphisms and diabetic retinopathy. Odds ratio (OR) and 95% confident interval (95% CI) were calculated. Generalized multifactor dimensionality reduction was employed to analyze the impact of interaction among three single nucleotide polymorphisms on CVD risk. After covariates adjustment, the carriers of homozygous mutant of three single nucleotide polymorphisms have higher diabetic retinopathy risk than those with wild-type homozygotes, OR (95% CI) were 2.04 (1.12-2.35), 1.87 (1.10-2.41) and 1.15 (1.06-1.76), respectively. Generalized multifactor dimensionality reduction model indicated a significant three-locus model (p = 0.0010) involving rs507392, rs1617640, and rs551238. Overall, the three-locus models had a cross-validation consistency of 10 of 10, and had the testing accuracy of 60.72%. Subjects with TC or CC-TG or GG-AC or CC genotype have the highest diabetic retinopathy risk. In conclusion, our results support an important association of rs507392, rs1617640 and rs551238 minor allele of erythropoietin with increased diabetic retinopathy risk, and additional interaction among three single nucleotide polymorphisms.

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Is PPARG the key gene in diabetic retinopathy?

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Is PPARG the key gene in diabetic retinopathy?

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