Abstract
Purpose :
Our previous studies demonstrated that increased expression of Ang-(1-7), the key member of the vasoprotective axis of the renin angiotensin system (RAS), via AAV-mediated retinal gene delivery, reduced diabetes-induced retinal pathology, providing the proof-of-concept that enhancing this axis is a promising approach for treating patients with DR. In addition, enhanced expression of Ang-(1-7) also improves lipid and glucose metabolism, ameliorates insulin resistance and confers protection against a variety of pathological conditions. Thus an ideal strategy would be to enhance this axis both systemically and locally at target tissues. This study was aimed to test the hypothesis that oral delivery of Ang-(1-7) bioencapsulated in plant cells would confer protection against diabetes-induced retinopathy in animal models.
Methods :
Ang-(1-7) peptide fused with non-toxic cholera toxin subunit B (CTB) was expressed in plant chloroplasts. Diabetic eNOS-/- mice induced by STZ and Akita mice were orally gavaged with wild-type or Ang-(1-7) leaf materials three times/week, for eight weeks.
Results :
Increased level of Ang-(1-7) was observed in circulation and retina after oral administration of CTB- Ang-(1-7). Ang (1-7) leaf material treatment significantly improved the glucose tolerance and insulin sensitivity in diabetic eNOS-/- and Akita mice, increased insulin expression of the pancreatic islets compared to control groups (untreated or treated with wild-type leaf material). Ang (1-7) leaf material treatment also significantly reduced apoptotic cell death in kidney, as well as diabetes- induced RGC loss, gliosis and microglial cell activation, expression of inflammatory cytokines in diabetic retina, improved mitochondrial function and prevented retinal endothelial capillary loss.
Conclusions :
Our results demonstrate that orally administered Ang-(1-7) bioencapsulated in plant cells can be efficiently delivered into circulation and target tissues; orally administered bioencapsulated Ang-(1-7) not only mitigated diabetic retinopathy, but also improved systemic parameters and other diabetic complications, thus enhancing the protective axis of RAS by oral delivery of Ang-(1–7) bioencapsulated in plant cells provide an innovative, highly efficient and cost-effective therapeutic strategy for treating diabetes and diabetic complications.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.