Work

Indoxyl sulfate induces retinal microvascular injury via COX-2/PGE2 activation in diabetic retinopathy

Year: 2024

Type: article

Abstract: Background Diabetic retinopathy (DR), the leading cause of acquired blindness in the working-age population, is the most frequent microvascular complication of diabetes. Metabolic disorders are thought to contribute to the pathogenicity, but the mechanism remains largely unknown. Methods To explore the mechanism, we first identified differences of vitreous fluid metabolite profiles between 23 patients with DR and 12 non-diabetic controls using liquid chromatography/tandem mass spectrometry, and screened out the most distinctive metabolite-indoxyl sulfate (IS). Next, streptozotocin (STZ)-induced diabetic and IS-injected rat models were established to validate IS effects on retinal microvascular. Then, RNA sequencing was performed to discover underlying regulators in IS-treated human retinal endothelium cells (HREC). Finally, target gene knockdown of HREC and IS-injected rats treated with inhibitors (for IS production or downstream regulator) were used to verify the detailed mechanism and explore therapeutic targets for DR. Results Metabolomics revealed 172 significantly differential metabolites in diabetic vitreous humor, including dysregulated tryptophan metabolites indoxyl sulfate (IS). IS was found to penetrate the blood-retinal barrier and accumulate in the intraocular fluid of diabetic rats. In vivo and in vitro experiments demonstrated that elevated IS caused endothelial apoptosis and cell junction breakdown. RNA sequencing identified prostaglandin E2 (PGE2) synthetase-cyclooxygenase 2 (COX-2) as the potential target of IS. Validation experiments showed IS promoted COX-2 expression and then PGE2 secretion by biding with COX-2 transcription factor EGR1 after entry into cells via organic anion transporting polypeptides (OATP2B1). Moreover, COX-2 inhibition in vivo or EGR1/OATP2B1 siRNA in HREC attenuated IS-induced microcapillary damage and COX-2/PGE2 activation. Conclusion Our study revealed that IS, a uremic toxin derived from gut microbiota product indole, increased significantly and contributed to retinal microvascular damage in DR. Mechanistically, IS impaired retinal microvascular by inducing COX-2 expression and PGE2 production. Targeting gut microbiota or the PGE2 pathway may be effective strategies for DR treatment.

Source: Journal of Translational Medicine

DOI: 10.1186/s12967-024-05654-1