Overexpression of protein kinase C ß2 in mouse vasculature induces retinal abnormalities characteristic of diabetic retinopathy without diabetes

Abstract

Abstract: : Purpose: PKC regulates numerous vascular functions including permeability, contractility, and cellular proliferation. In vascular cells and various tissues including the retina, the PKC ß2 isoform is preferentially activated by diabetes. The inhibition of PKC ß can normalize diabetes–induced alterations of permeability, retinal blood flow and retinal neovascularization. In this study, we investigate whether the overexpression of PKC ß2 in the vasculature can induce retinopathy–like pathology in nondiabetic mice. Methods: Vascular specific overexpression of PKC ß2 in transgenic FVB mice was obtained using a preproET–1 promoter with PKC ß2 cDNA construct. Expression of the transgene product was present in the vessel wall. Non–diabetic and STZ–induced (90mg/kg) diabetic transgenic (Tg) and wild type (WT) mice at 6 months of age underwent fluorescein angiography to detect retinal lesions. Lesions were confirmed by fluorescein dextran (2,000 kDa) retinal flatmounts using confocal microscopy and by trypsin digest. Retinal vascular permeability (RVP) was measured by Evan’s blue albumin permeation. Results: Retinal vascular abnormalities were observed in NDM and DM Tg mice but not in NDM or DM WT mice. Retinal abnormalities included venous changes (loops, beading, and caliber irregularity) and aneurismal like lesions. Retinal lesions occurred in 76% (16/21) and 67% (8/12) of NDM and DM Tg mice, respectively. No retinal lesions were observed in DM (0/6) or NDM (0/10) WT animals. RVP was increased by 70% in DM WT (1.7±1.0, p<0.05) and by 60% in NDM Tg (1.6±1.0, p=0.036) as compared to NDM WT (1.0±0.6). Conclusions: Nondiabetic transgenic mice overexpressing PKC ß2 in the vasculature exhibit decreased retinal blood flow, increased RVP, and retinal vascular lesions characteristic of diabetes. These observations suggest that activation of PKC ß2 in the retinal vasculature directly contribute to the development of early diabetic retinopathy.

Keywords: transgenics/knock–outs • diabetic retinopathy • pathology: experimental