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J. K. Sun, P. Geraldes, H. Keenan, M. Matsumoto, L. P. Aiello, G. L. King; Decreased SHP-1 Expression is Associated With Protection From Diabetic Retinopathy Despite Poor Glycemic Control in Patients With 50 Years or More of Diabetes. Invest. Ophthalmol. Vis. Sci. 2010;51(13):5845.
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We recently published (Nat Med 2009) that hyperglycemia increases expression of PKCdelta (PKCd) and subsequently a new marker, SHP-1, resulting in acellular capillaries and pericyte apoptosis, both early findings in diabetic retinopathy (DR). This study evaluates the role of PKCd and SHP-1 in vitro and for the first time in vivo, in individuals protected against vascular complications despite 50 years or more of diabetes (Joslin Medalists).
Gene and mRNA expression of SHP-1 were assessed in peripheral blood mononuclear cells (PBMC) from Zucker lean (ZL) and Zucker diabetic (ZD) rats. Cells were used directly or incubated with or without GF109203X (GFX), a general PKC inhibitor, for 10 hours. PBMC mRNA levels of SHP-1 and PKCd were evaluated in 187 Medalists characterized for diabetic complication status, including DR (assessed on ETDRS-protocol 7 standard field stereoscopic fundus images), nephropathy, neuropathy, and cardiovascular disease.
SHP-1 gene expression was increased 94% (p=0.001) in ZD after 8 weeks of diabetes as compared to ZL. SHP-1 mRNA levels in ZD rats increased by 1.9-fold (p=0.01) compared with ZL. Treatment with GFX reduced SHP-1 mRNA expression in ZD rats by 42% (p< 0.05). Both SHP-1 and PKCd levels were significantly decreased (SHP-1 by 35%, p=0.03; PKCd by 58%, p=0.02) in Medalists who remained free of advanced DR despite poor glycemic control (HbA1c≥7.6%) compared to the remainder of the Medalist cohort. SHP-1 and PKCd were also consistently decreased in Medalists free of nephropathy (SHP-1: 28%, p=0.04; PKCd: 29%, p=0.13), neuropathy (SHP-1: 31%, p=0.13, PKCd: 31%, p=0.23), and cardiovascular disease (SHP-1: 69%, p=0.01; PKCd: 53%, p<0.05) in the setting of high HbA1c as compared with the rest of the group.
Diabetes-induced SHP-1 expression is partially normalized by PKC inhibition. In addition, SHP-1 is decreased in human subjects protected from DR even after extended diabetes duration and current poor glycemic control. These data suggest that mechanisms suppressing SHP-1 expression may be protective against hyperglycemia-induced retinal pathology.
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