Genetically modified probiotics for oral delivery of Angiotensin-(1-7) confers protection against diabetic complications

Abstract

Purpose : Previous studies have established that activation of the members of the vasoprotective axis of the renin-angiotensin system [ACE2 or Angiotensin-(1-7) (Ang-(1-7)] prevents and arrests progression of diabetic retinopathy. The objective of present study was to generate a probiotic containing Ang-(1-7) and test the hypothesis that oral administration of such a probiotic would provide protection against diabetic retinopathy.

Methods : We genetically modified the commensal bacterium Lactobacillus paracasei (LP) to serve as a live vector for the oral delivery of Ang-(1-7) and investigated its therapeutic potential in attenuating diabetes and associated complications. Ang-(1-7) was expressed as a secreted fusion protein with a trans-epithelial carrier to allow uptake into circulation. The vector pTRKH3-ldh-SP-Ang-(1-7) or pTRKH3-ldh-GFP were introduced by electroporation into LP. Two-month old adult diabetic eNOS-/- mice induced by intraperitoneal injection of streptozotocin and Akita mice were orally gavaged every other day with 1x10⁹ CFU of LP secreting Ang-(1-7) (LP-A), LP secreting GFP (LP-GFP), or LP alone for eight and twelve weeks respectively.

Results : Compared to age-matched untreated diabetic control animals, oral feeding of LP and LP-A significantly improved STZ-induced damage to insulin producing beta cells in pancreas in diabetic eNOS-/- mice. LP-A treatment also enhanced glucose tolerance, improved structure and morphology of islets and kidney, increased insulin expression in both diabetic eNOS-/- mice and Akita mice; and are associated with reduced retinal gliosis, inflammation, apoptotic neuronal cell death and loss of retinal vascular capillaries.

Conclusions : Oral administration of a genetically modified commensal bacterium that can secrete Ang-(1-7) provides protection against diabetes-induced tissue damage and diabetic retinopathy. Thus, LP-based delivery of Ang-(1-7) may hold important therapeutic potential for the treatment of diabetic complication.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.