BADERC- Mara Lorenzi

Mara Lorenzi, M.D.

Pathogenesis of Nonproliferative Diabetic Retinopathy

The interest of the laboratory is to reconstruct the cellular and molecular events by which diabetes leads to retinal capillary damage. The early changes induced by diabetes in retinal capillaries set the stage for abnormal vascular permeability that may culminate in macular edema, and for vessel closure/obliteration that lead to retinal ischemia and the sight-threatening proliferative stage of diabetic retinopathy. We have identified in both human and experimental diabetic retinopathy several processes operative at early stages, and with the potential to account for the late lesions. These are accelerated apoptosis of both pericytes and endothelial cells of the retinal capillaries, microthrombosis, and complement activation. In order to understand how diabetes and/or high glucose levels affect the internal and external environment of microvascular cells in ways that favor the occurrence of the above processes, studies address (i) the activation of transcription factors that elicit biosynthetic programs with apoptogenic potential, (ii) the regulation of intracellular modulators of apoptosis, (iii) the availability of retinal growth and survival factors; (iv) the undermining of mechanisms that protect the luminal endothelial surface from inflammation and thrombosis, and (v) abnormalities in retinal glial cells that may impact on vascular homeostasis. The experimental approach combines studies in cultured cells and in retinas and retinal microvessels isolated from diabetic patients and animal models of diabetic retinopathy. The ultimate goal is to identify discrete molecular events with a proven pathogenetic role that can become rational targets for intervention.

References:

1. Mizutani M, Kern TS, Lorenzi M. Accelerated death of retinal microvascular cells in human and experimental diabetic retinopathy. J Clin Invest 1996; 97:2883-2890.

2. Gerhardinger C, McClure KD, Romeo G, Podestà F, Lorenzi M. IGF-I mRNA and signaling in the diabetic retina. Diabetes 2001; 50:175-183.

3. Boeri D*, Maiello M*, Lorenzi M. Increased prevalence of microthromboses in retinal capillaries of diabetic individuals. (*co-first authors). Diabetes 2001; 50:1432-1439.

4. Romeo G*, Liu W-H*, Asnaghi V, Kern TS, Lorenzi M. Activation of nuclear factor-kB induced by diabetes and high glucose regulates a proapoptotic program in retinal pericytes. (*co-first authors). Diabetes 2002; 51:2241-2248.

5. Zhang J, Gerhardinger C, Lorenzi M. Early complement activation and decreased levels of glycosylphosphatidylinositol-anchored complement inhibitors in human and experimental diabetic retinopathy. Diabetes 2002; 51:3499-3504.

6. Asnaghi V, Gerhardinger C, Hoehn T, Adeboje A, Lorenzi M. A role for the polyol pathway in the early neuroretinal apoptosis and glial changes induced by diabetes in the rat. Diabetes 2003; 52:506-511.






			Mara Lorenzi, M.D. Pathogenesis of Nonproliferative Diabetic Retinopathy The interest of the laboratory is to reconstruct the cellular and molecular events by which diabetes leads to retinal capillary damage. The early changes induced by diabetes in retinal capillaries set the stage for abnormal vascular permeability that may culminate in macular edema, and for vessel closure/obliteration that lead to retinal ischemia and the sight-threatening proliferative stage of diabetic retinopathy. We have identified in both human and experimental diabetic retinopathy several processes operative at early stages, and with the potential to account for the late lesions. These are accelerated apoptosis of both pericytes and endothelial cells of the retinal capillaries, microthrombosis, and complement activation. In order to understand how diabetes and/or high glucose levels affect the internal and external environment of microvascular cells in ways that favor the occurrence of the above processes, studies address (i) the activation of transcription factors that elicit biosynthetic programs with apoptogenic potential, (ii) the regulation of intracellular modulators of apoptosis, (iii) the availability of retinal growth and survival factors; (iv) the undermining of mechanisms that protect the luminal endothelial surface from inflammation and thrombosis, and (v) abnormalities in retinal glial cells that may impact on vascular homeostasis. The experimental approach combines studies in cultured cells and in retinas and retinal microvessels isolated from diabetic patients and animal models of diabetic retinopathy. The ultimate goal is to identify discrete molecular events with a proven pathogenetic role that can become rational targets for intervention. References: 1. Mizutani M, Kern TS, Lorenzi M. Accelerated death of retinal microvascular cells in human and experimental diabetic retinopathy. J Clin Invest 1996; 97:2883-2890. 2. Gerhardinger C, McClure KD, Romeo G, Podestà F, Lorenzi M. IGF-I mRNA and signaling in the diabetic retina. Diabetes 2001; 50:175-183. 3. Boeri D, Maiello M, Lorenzi M. Increased prevalence of microthromboses in retinal capillaries of diabetic individuals. (co-first authors). Diabetes 2001; 50:1432-1439. 4. Romeo G, Liu W-H, Asnaghi V, Kern TS, Lorenzi M. Activation of nuclear factor-kB induced by diabetes and high glucose regulates a proapoptotic program in retinal pericytes. (co-first authors). Diabetes 2002; 51:2241-2248. 5. Zhang J, Gerhardinger C, Lorenzi M. Early complement activation and decreased levels of glycosylphosphatidylinositol-anchored complement inhibitors in human and experimental diabetic retinopathy. Diabetes 2002; 51:3499-3504. 6. Asnaghi V, Gerhardinger C, Hoehn T, Adeboje A, Lorenzi M. A role for the polyol pathway in the early neuroretinal apoptosis and glial changes induced by diabetes in the rat. Diabetes 2003; 52:506-511.