Recombinant Probiotics Expressing Angiotensin-(1-7) Improves Glucose Metabolism and Diabetes-Induced Renal and Retinal Injury

Purpose: Multitude of animal studies substantiate the beneficial effects of Ang-(1-7) in diabetes and associated complications. However, the biggest impediment to translate this into clinical application is large-scale production of high quality Ang-(1-7) with enhanced tissue bioavailability. As emerging evidence also implicates the beneficial effects of probiotics in managing diabetes, this study aimed to test the hypothesis that oral delivery of recombinant probiotics expressing Ang-(1-7) will improve glucose metabolism and diabetes-induced tissue damage in animal models. Method: Ang-(1-7) was expressed as a secreted fusion protein with a transepithelial carrier in Lactobacillus paracasei (LP) to allow uptake into circulation and target tissues. Adult diabetic eNOS -/- mice were orally gavaged daily with 1x10 9 CFU of LP secreting Ang-(1-7) (LP-A), or LP alone for eight weeks. Glucose metabolism and tissues were assessed using standard assays and histochemical techniques. Result: Oral feeding of LP-A significantly lowered fasted-state blood glucose (P=0.042); improved the intraperitoneal glucose tolerance test (P=0.034) than control mice. LP-A-treated mice showed higher plasma insulin level (P=0.028) and insulin expression in islets β cells compared to control mice. LP-A treatment significantly reduced apoptotic cell death in kidney, improved diabetes-induced collagen deposits in the glomerular tuft and the tubular epithelia in diabetic mice. LP-A treatment also significantly reduced retinal gliosis, inflammation, neuronal cell death and loss of retinal vascular capillaries. Conclusion: Oral administration of recombinant probiotics secreting Ang-(1-7) improved glucose tolerance by enhancing insulin level, and reduced diabetes-induced damage in kidney and retina. Thus, recombinant probiotics-based delivery of Ang-(1-7) may hold promising therapeutic potential for diabetes and associated complications. Disclosure Q. Li: None. K. Xu: None. T. Du: None. P. Zhu: None. A. Verma: None.