IGF-I mRNA and Signaling in the Diabetic Retina
- From the Schepens Eye Research Institute (C.G., K.D.M., G.R., F.P., M.L.) and the Department of Ophthalmology (C.G., G.R., F.P., M.L.), Harvard Medical School, Boston, Massachusetts.
- Address correspondence and reprint requests to Mara Lorenzi, MD, Schepens Eye Research Institute, 20 Staniford St., Boston, MA 02114. E-mail: lorenzi{at}vision.eri.harvard.edu .
Abstract
IGF-I promotes the survival of multiple cell types by activating the IGF-I receptor (IGF-IR), which signals downstream to a serine/threonine kinase termed Akt. Because in diabetes vascular and neural cells of the retina undergo accelerated apoptosis, we examined IGF-I synthesis and signaling in the human and rat diabetic retina. In retinas obtained postmortem from six donors aged 64 ± 8 years with a diabetes duration of 7 ± 5 years, IGF-I mRNA levels were threefold lower than in the retinas of six age-matched nondiabetic donors (P = 0.005). In the retinas of rats with 2 months' duration of streptozotocin-induced diabetes, IGF-I mRNA levels were similar to those of control rats, but after 5 months of diabetes they failed to increase to the levels recorded in age-matched controls (P < 0.02). Retinal IGF-I expression was not altered by hypophysectomy, proving to be growth-hormone independent. IGF-IR levels were modestly increased in the human diabetic retinas (P = 0.02 vs. nondiabetic retinas) and were unchanged in the diabetic rats. Phosphorylation of the IGF-IR could be measured only in the rat retina, and was not decreased in the diabetic rats (94 ± 18% of control values). In the same diabetic rats, phosphorylation of Akt was 123 ± 21% of control values. There was not yet evidence of increased apoptosis of retinal microvascular cells after 5 months of streptozotocin-induced diabetes. Hence, in the retina of diabetic rats, as in the retina of diabetic human donors, IGF-I mRNA levels are substantially lower than in age-matched nondiabetic controls, whereas IGF-IR activation and signaling are not affected, at least for some time. This finding suggests that in the diabetic retina, the activation of the IGF-IR is modulated by influences that compensate for, or are compensated by, decreased IGF-I synthesis.
Footnotes
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BSA, bovine serum albumin; C-RT-PCR, competitive reverse transcriptase—polymerase chain reaction; IGF-IR, IGF-I receptor; PCR, polymerase chain reaction; TBST, Tris-buffered saline containing 0.05% Tween-20; TUNEL, terminal deoxynucleotidyl transferase—mediated dUTP nick-end labeling.
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- Accepted September 20, 2000.
- Received March 9, 2000.
- by the American Diabetes Association, Inc.
