Diabetic retinopathy (DR) is a significant cause of blindness in working-age adults worldwide. Lack of effective strategies to prevent or reduce vision loss is a major problem. Since the degeneration of retinal neurons is an early event in the diabetic retina, studies to characterize the molecular mechanisms of diabetes-induced retinal neuronal damage and dysfunction are of high significance. We have demonstrated that spermine oxidase (SMOX), a mediator of polyamine oxidation is critically involved in causing neurovascular damage in the retina. The involvement of SMOX in diabetes-induced retinal neuronal damage is completely unknown. Utilizing the streptozotocin-induced mouse model of diabetes, the impact of the SMOX inhibitor, MDL 72527, on neuronal damage and dysfunction in the diabetic retina was investigated. Retinal function was assessed by electroretinography (ERG) and retinal architecture was evaluated using spectral domain-optical coherence tomography. Retinal cryosections were prepared for immunolabeling of inner retinal neurons and retinal lysates were used for Western blotting. We observed a marked decrease in retinal function in diabetic mice compared to the non-diabetic controls. Treatment with MDL 72527 significantly improved the ERG responses in diabetic retinas. Diabetes-induced retinal thinning was also inhibited by the MDL 72527 treatment. Our analysis further showed that diabetes-induced retinal ganglion cell damage and neurodegeneration were markedly attenuated by MDL 72527 treatment. These results strongly implicate SMOX in diabetes-induced retinal neurodegeneration and visual dysfunction.

Ocular diseases such as diabetic retinopathy (DR) and uveitis are associated with injury to the blood–retinal barrier (BRB). Whereas high glucose (HG) and advanced glycation end products (AGE) contribute to DR, bacterial infections causing uveitis are triggered by endotoxins such as lipopolysaccharide (LPS). It is unclear how HG, AGE, and LPS affect human retinal endothelial cell (HREC) junctions. Moreover, tumor necrosis factor-α (TNFα) is elevated in both DR and ocular infections. In the current study, we determined the direct effects of HG, AGE, TNFα, and LPS on the expression and intracellular distribution of claudin-5, VE-cadherin, and β-catenin in HRECs and how these mediators affect Akt and P38 MAP kinase that have been implicated in ocular pathologies. In our results, whereas HG, AGE, and TNFα activated both Akt and P38 MAPK, LPS treatment suppressed Akt but increased P38 MAPK phosphorylation. Furthermore, while treatment with AGE and HG increased cell-junction protein expression in HRECs, LPS elicited a paradoxical effect. By contrast, when HG treatment increased HREC-barrier resistance, AGE and LPS stimulation compromised it, and TNFα had no effect. Together, our results demonstrated the differential effects of the mediators of diabetes and infection on HREC-barrier modulation leading to BRB injury.

The multi-gene claudin (CLDN) family of tight junction proteins have isoform-specific roles in blood–tissue barrier regulation. CLDN17, a putative anion pore-forming CLDN based on its structural characterization, is assumed to regulate anion balance across the blood-tissue barriers. However, our knowledge about CLDN17 in physiology and pathology is limited. The current study investigated how Cldn17 deficiency in mice affects blood electrolytes and kidney structure. Cldn17^−/− mice revealed no breeding abnormalities, but the newborn pups exhibited delayed growth. Adult Cldn17^−/− mice displayed electrolyte imbalance, oxidative stress, and injury to the kidneys. Ingenuity pathway analysis followed by RNA-sequencing revealed hyperactivation of signaling pathways and downregulation of SOD1 expression in kidneys associated with inflammation and reactive oxygen species generation, demonstrating the importance of Cldn17 in the maintenance of electrolytes and reactive oxygen species across the blood-tissue barrier.