Sitagliptin and the Blood-Retina Barrier: Effects on Retinal Endothelial Cells Manifested Only after Prolonged...

Current treatments for diabetes include DPP-4 inhibitors, which modulate glucose metabolism. However, their impact on retinal endothelial cell barrier function remains unclear. Prior research has shown that these drugs can influence vascular permeability, but findings are inconsistent. This uncertainty drives the need for more precise studies on how DPP-4 inhibitors affect retinal endothelial cells. Existing knowledge suggests that VEGF-A is a major contributor to retinal edema in diabetic patients. Yet, the interaction between DPP-4 inhibitors and VEGF-A in this context is not fully understood. No prior work has resolved whether DPP-4 inhibitors can stabilize or destabilize the retinal barrier over time. This gap motivates investigations into the long-term effects of DPP-4 inhibitors on endothelial cell function. Understanding these effects is critical for assessing the safety of these drugs in diabetic patients at risk of retinal complications.

This study aimed to assess whether DPP-4 inhibitors, such as sitagliptin and diprotin A, influence the barrier properties of retinal endothelial cells. The researchers focused on the long-term effects of these inhibitors on cell stability and adhesion. They also sought to determine if these drugs could counteract or enhance the effects of VEGF-A on retinal permeability. The motivation for this study comes from the clinical need to understand how diabetes treatments might affect retinal health. Existing evidence is conflicting, so a detailed investigation was necessary. The study used an in vitro model of bovine retinal endothelial cells to monitor changes over time. By measuring cell index and protein expression, the researchers aimed to detect subtle changes in barrier integrity. This approach allows for a more nuanced understanding of how DPP-4 inhibition affects retinal endothelial function.

The researchers used immortalized bovine retinal endothelial cells (iBREC) grown on gold electrodes to monitor cell index continuously. They tested sitagliptin and diprotin A at concentrations ranging from 10 to 1000 nM and 1 to 25 μM, respectively. The effects of these inhibitors were also evaluated in the presence of VEGF-A₁₆₅ to simulate diabetic conditions. Cell index was measured over time to detect changes in paracellular and transcellular flow. Protein expression levels of claudin-1, CD29, and CD9 were analyzed to assess barrier and adhesion properties. The study included a time-dependent analysis to capture delayed effects of the inhibitors. No prior modulation of VEGF-A-induced permeability was observed with either drug. The experimental design allowed for the detection of subtle or transient changes in endothelial cell behavior.

Sitagliptin and diprotin A caused a significant and persistent decline in cell index at 40 and 55 hours, respectively. Neither drug modulated or reversed the VEGF-A₁₆₅-induced reduction in cell index. Both inhibitors increased the expression of claudin-1, a key tight-junction protein. However, CD29 and CD9 expression decreased after prolonged exposure to the DPP-4 inhibitors. CD9 was notably reduced at the plasma membrane after extended sitagliptin treatment. These findings suggest that DPP-4 inhibition weakens cell adhesion to the extracellular matrix. The observed changes in protein expression correlate with the decline in cell index. These results indicate that long-term DPP-4 inhibition may destabilize the retinal endothelial barrier.

The authors conclude that prolonged DPP-4 inhibition destabilizes the barrier formed by retinal endothelial cells. This effect was observed as a persistent decline in cell index after 40–55 hours of treatment. Neither sitagliptin nor diprotin A counteracted or enhanced VEGF-A-induced permeability. The increase in claudin-1 expression did not prevent the overall decline in barrier stability. Reduced CD29 and CD9 expression suggests impaired cell adhesion to the extracellular matrix. These findings highlight the potential risks of long-term DPP-4 inhibitor use in diabetic patients. The observed effects are specific to the in vitro model used in this study. The results support the need for further research into the ocular effects of DPP-4 inhibitors in clinical settings.