Mara Lorenzi, M.D.

Molecular mechanisms underlying Diabetic Retinopathy

My lab has focused on investigating mechanisms for diabetic retinopathy, with emphasis on the molecular and cellular aspects of human diabetic retinopathy. We tested in vivo the concept of glucose toxicity that we had formulated using cultured endothelial cells, and observed that the effect of diabetes on the gene expression of retinal vascular cells is remarkably similar to the program induced by high glucose in vitro. By documenting in human diabetic retinal vessels accelerated apoptosis of microvascular cells, complement activation, and microthrombosis, we provided mechanisms for the “pericyte drop-out” and “acellular capillaries” that are the histological hallmarks of diabetic retinopathy. We uncovered that not only the vessels are affected by diabetes in the retina. Müller glial cells acquire early in the course of both human and experimental diabetes a reactive phenotype.

The current focus is on strategies to prevent diabetic retinopathy. We use preclinical models to isolate molecular processes that are causally related to retinopathy and could become target of adjunct drugs in humans. In view of the long latency period between the onset of diabetes and the appearance of the classical vascular lesions of retinopathy, we have also begun to investigate the hypothesis that there may be protective mechanisms operative on the vessels, at least after short diabetes duration. One such mechanism may rests on the patroller monocytes, which would couple to their surveillance activity the delivery of vasculo-protective and anti-inflammatory cytokines.

To facilitate the development of adjunct drugs to pre-empt the development of clinical retinopathy, we also seek to identify in diabetic patients early markers of retinopathy risk. We have recently identified a candidate risk marker to be brought to validation.

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. PMCID: PMC507384

2. Dagher Z, Park YS, Asnaghi V, Hoehn T, Gerhardinger C, Lorenzi M: Studies of rat and human retinas predict a role for the polyol pathway in human diabetic retinopathy. Diabetes 2004; 53:2404-2411

3. Sun W, Gerhardinger C, Dagher Z, Hoehn T, Lorenzi M: Aspirin at low-intermediate concentrations protects retinal vessels in experimental diabetic retinopathy through non-platelet-mediated effects. Diabetes 2005; 54:3418-3426.

4. Gerhardinger C, Dagher Z, Sebastiani P, Park Y-S, Lorenzi M: The transforming growth factor-β pathway is a common target of drugs that prevent experimental diabetic retinopathy. Diabetes 2009; 58:1659-1667. PMCID: PMC2699853

5. Lorenzi M, Feke GT, Pitler L, Berisha F, Kolodjaschna J, McMeel JW: Defective myogenic response to posture change in retinal vessels of well-controlled type 1 diabetic patients without retinopathy. Invest Ophthalmol Vis Sci 2010; 51:6770-6775.

6. Zerbini G, Maestroni A, Palini A, Tremolada G, Lattanzio R, Maestroni S, Pastore MR, Secchi A, Bonfanti R, Gerhardinger C, Lorenzi M: Endothelial progenitor cells carrying monocyte markers are selectively abnormal in type 1 diabetic patients with early retinopathy. Diabetes 2012; 61:908-914. PMCID: PMC3314367.

 

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