The retina is highly sensitive to oxygen and blood supply, and hypoxia plays a key role in retinal diseases such as diabetic retinopathy (DR) and age-related macular degeneration (AMD). Müller glial cells, which are essential for retinal homeostasis, respond to injury and hypoxia with reactive gliosis, characterized by the upregulation of the glial fibrillary acidic protein (GFAP) and vimentin, cellular hypertrophy, and extracellular matrix changes, which can impair retinal function and repair. The retinal pigment epithelium (RPE) supports photoreceptors, forms part of the blood–retinal barrier, and protects against oxidative stress; its dysfunction contributes to retinal degenerative diseases such as AMD, retinitis pigmentosa (RP), and Stargardt disease (SD). Extracellular vesicles (EVs) play a crucial role in intercellular communication, protein homeostasis, and immune modulation, and have emerged as promising diagnostic and therapeutic tools. Understanding the role of extracellular vesicles’ (EVs’) signaling machinery of glial cells and the retinal pigment epithelium (RPE) is critical for developing effective treatments for retinal degeneration. In this study, we investigated the bidirectional EV-mediated crosstalk between RPE and Müller cells under hypoxic conditions and its impact on cellular metabolism and retinal cell integrity. Our findings demonstrate that RPE-derived extracellular vesicles (RPE EVs) induce time-dependent metabolic reprogramming in Müller cells. Short-term exposure (24 h) promotes pathways supporting neurotransmitter cycling, calcium and mineral absorption, and glutamate metabolism, while prolonged exposure (72 h) shifts Müller cell metabolism toward enhanced mitochondrial function and ATP production. Conversely, Müller cell-derived EVs under hypoxia influenced RPE metabolic pathways, enhancing fatty acid metabolism, intracellular vesicular trafficking, and the biosynthesis of mitochondrial co-factors such as ubiquinone. Proteomic analysis revealed significant modulation of key regulatory proteins. In Müller cells, hypoxic RPE-EV exposure led to reduced expression of Dyskerin Pseudouridine Synthase 1 (DKc1), Eukaryotic Translation Termination Factor 1 (ETF1), and Protein Ser/Thr phosphatases (PPP2R1B), suggesting alterations in RNA processing, translational fidelity, and signaling. RPE cells exposed to hypoxic Müller cell EVs exhibited elevated Ribosome-binding protein 1 (RRBP1), RAC1/2, and Guanine Nucleotide-Binding Protein G(i) Subunit Alpha-1 (GNAI1), supporting enhanced endoplasmic reticulum (ER) function and cytoskeletal remodeling. Functional assays also revealed the compromised barrier integrity of the outer blood–retinal barrier (oBRB) under hypoxic co-culture conditions. These results underscore the adaptive but time-sensitive nature of retinal cell communication via EVs in response to hypoxia. Targeting this crosstalk may offer novel therapeutic strategies to preserve retinal structure and function in ischemic retinopathies.

Background: Obesity is a major contributor to chronic kidney disease (CKD) through mechanisms involving inflammation and metabolic dysregulation. Premenopausal female rats are known to be protected from cardiovascular disorders vs. age matched male rats. The current study investigates if there are sex differences in obesity-induced renal inflammation in SS leptin receptor mutant (SS^LepR mutant) rats as a model of metabolic syndrome. Method: Male and female lean and obese SS^LepR mutant rats were used in the current study to assess changes in metabolic parameters and markers of renal inflammation. Results: Obese SS^LepR rats showed significant increases in body weight, hemoglobin A1c (HbA1c), and cholesterol vs. lean control, although their blood glucose levels remained comparable to lean rats. Plasma leptin, insulin, and TNF-α converting enzyme (TACE) levels were significantly elevated in obese SS^LepR rats vs. lean control rats, with no apparent sex differences. Obesity was associated with an elevation in renal injury since protein and albumin excretion levels were significantly elevated in obese SS^LepR rats vs. lean control rats, with no apparent sex differences. The elevation in renal injury was associated with increased renal fibrosis as evidenced by increased collagen deposition and TGF-β expression in the kidney of obese SS^LepR rats vs. lean control rats. Increased renal fibrosis also coincided with increased renal inflammation and apoptosis as evidenced by increased macrophage infiltration and IL-6 expression in the kidneys of obese SS^LepR rats vs. lean control rats. Conclusion: These findings indicate that obesity triggers renal inflammation and fibrosis independent of hyperglycemia in SS^LepR rats, and these changes may override sex-based protective effects seen in females in other experimental rodent models of cardiovascular diseases.

Diabetes mellitus represents a major global health challenge with rapidly increasing prevalence and substantial morbidity driven by metabolic and vascular complications. Extracellular vesicles (EVs) have emerged as critical mediators of intercellular communication and are increasingly implicated in the pathogenesis and progression of diabetes. This review summarizes current knowledge on EV biology, including their classification, cellular sources, biogenesis, uptake mechanisms, and molecular cargo. We discuss the contribution of EV-associated microRNAs to immune dysregulation and β-cell damage in type 1 diabetes mellitus (T1DM), as well as the role of EVs in insulin resistance, metabolic signaling, and vascular dysfunction in type 2 diabetes mellitus (T2DM). Particular emphasis is placed on EV-mediated modulation of endothelial function, angiogenesis, and tissue repair, alongside their involvement in the impairment of insulin receptor integrity. We further explore how lifestyle factors may influence EV composition and function, highlighting their potential integration into preventive strategies. Finally, we evaluate the emerging therapeutic potential of EVs as biomarkers and delivery systems, while addressing current limitations and future directions. Collectively, EVs represent a promising frontier in understanding diabetes pathophysiology and developing innovative diagnostic and therapeutic approaches. Unlike previous reviews that examine EVs separately as biomarkers or therapeutic vehicles, this review integrates emerging evidence supporting EVs as mediators of systemic communication linking pancreatic islets, adipose tissue, immune cells, vascular endothelium, kidney, heart, and retina throughout diabetes progression. We further critically evaluate translational barriers that currently limit clinical implementation of EV-based diagnostics and therapeutics.

The retina is highly sensitive to oxygen and blood supply, and hypoxia plays a key role in retinal diseases such as diabetic retinopathy (DR) and age-related macular degeneration (AMD). Müller glial cells, essential for retinal homeostasis, respond to injury and hypoxia with reactive gliosis, characterized by upregulation of Glial Fibrillary Acidic Protein (GFAP) and vimentin, cellular hypertrophy, and extracellular matrix changes, which can impair retinal function and repair. The retinal pigment epithelium (RPE) supports photoreceptors, forms part of the blood-retinal barrier, and protects against oxidative stress; its dysfunction contributes to retinal degenerative diseases such as AMD, retinitis pigmentosa (RP), and Stargardt disease (SD).

Diabetic retinopathy (DR) is a leading cause of vision loss among working-age adults and is characterized by progressive retinal microvascular dysfunction driven by hyperglycemia-induced inflammation and oxidative stress. Histone deacetylase 6 (HDAC6), a cytoplasmic deacetylase involved in multiple cellular processes, has been implicated in vascular pathology; however, its specific role in retinal endothelial cells remains unclear. In this study, we investigated whether endothelial-specific deletion of HDAC6 protects against diabetic retinal injury. Endothelial HDAC6 knockout mice were generated using VE-cadherin–Cre recombination and subjected to streptozotocin-induced diabetes. Retinal vascular integrity, inflammatory and oxidative stress responses, endothelial senescence, and visual function were assessed during the course of hyperglycemia. Diabetic control mice developed characteristic features of DR, including vascular dysfunction, heightened inflammatory and oxidative stress responses, increased endothelial senescence, and impaired visual function. In contrast, endothelial-specific HDAC6 deletion markedly attenuated these pathological changes, preserving retinal vascular integrity and visual performance while reducing oxidative stress and inflammation. These findings identify endothelial HDAC6 as a key contributor to diabetes-induced retinal vascular injury and suggest that targeting endothelial HDAC6 may represent a promising therapeutic strategy for preventing microvascular damage and vision loss in DR.