Abstract
BackgroundInflammatory reaction in the dysfunction of retinal endotheliocytes has been considered to play a vital role in diabetic retinopathy (DR). Anti-inflammatory therapy so far gains poor outcome as DR treatment. This study aims to identify a novel therapeutic target of DR from the OMICs studies of a traditional anti-DR botanical products TNTL.MethodsHyperglycemic mice were treated with TNTL. The anti-hyperglycemic effect of TNTL was validated to confirm the biological consistency of the herbal products from batches. Improvement of DR by TNTL was examined by various assays on the retina. Next-generation transcriptome sequencing and cytokine array was used to identify the therapeutic targets. In vitro study was performed to validate the target.ResultsWe observed that TNTL at its high doses possessed anti-hyperglycemic effect in murine type I diabetic model, while at its doses without reducing blood glucose, it suppressed DR incidence. TNTL restored the blood-retina barrier integrity, suppressed retinal neovascularization, and attenuated the retinal ganglion cell degeneration. Transcriptomic analysis on the retina tissue of hyperglycemic mice with or without TNTL revealed that the inflammatory retina microenvironment was significantly repressed. TNTL treatment suppressed pro-inflammatory macrophages in the retina, which resulted in the inactivation of endothelial cell migration, restoration of endothelial cell monolayer integrity, and prevention of leakage. Cytokine array analysis suggested that TNTL could significantly inhibit the secretion of MIP1γ from pro-inflammatory macrophages. Prevention of endothelial dysfunction by TNTL may be mediated by the inhibition of MIP1γ/CCR1 axis. More specifically, TNTL suppressed MIP1γ release from pro-inflammatory macrophages, which in turn inhibited the activation of CCR1-associated signaling pathways in endothelial cells.ConclusionOur findings demonstrated that TNTL might be an alternative treatment to DR, and the primary source of potential drug candidates against DR targeting MIP1γ/CCR1 axis in the retinal microenvironment.
Highlights
Inflammatory reaction in the dysfunction of retinal endotheliocytes has been considered to play a vital role in diabetic retinopathy (DR)
Mice were continuously injected with a low dose of STZ (55 mg/kg, i.p.) for 5 days, and those with fasting blood glucose (FBG) within 15 to 20 mmol/L were treated with different doses of TNTL
It was found that oral TNTL treatment had minimal impact on the body weight of diabetic mice (Fig. 1a) but exhibited the dose-dependent manner in reducing the random blood glucose (RBG) of diabetic mice (Fig. 1b)
Summary
Inflammatory reaction in the dysfunction of retinal endotheliocytes has been considered to play a vital role in diabetic retinopathy (DR). Anti-inflammatory therapy so far gains poor outcome as DR treatment. Accumulation of VEGF in retina stimulates the generation of neovascularization as well as leakage of neighboring capillaries, which contributes to the blurred vision and eventually retinal damage [5]. Given its critical role in the pathological progression of DR, anti-VEGF treatment has been used to reduce neovascularization, though both panretinal photocoagulation and vitrectomy are yet the firstline and effective available therapy for DR [6]. AntiVEGF treatment, majorly consisting of various antibodies to VEGF analogs, is useful but failed to be longterm economically affordable due to its considerable cost for DR patients. Chronic patients were found not well responsive to anti-VEGF treatment [3]
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