May 2008
Volume 49, Issue 13
Free
ARVO Annual Meeting Abstract  |   May 2008
Activation of PKC Delta and P38 Alpha MAPK by Hyperglycemia - Novel Mechanism of Glycemic Memory in Diabetic Retinopathy
Author Affiliations & Notes
  • P. M. Geraldes
    Research, Joslin Diabetes Center, Boston, Massachusetts
  • T. S. Kern
    Research, Case Western Reserve University, Cleveland, Ohio
  • G. L. King
    Research, Joslin Diabetes Center, Boston, Massachusetts
  • Footnotes
    Commercial Relationships  P.M. Geraldes, None; T.S. Kern, None; G.L. King, None.
  • Footnotes
    Support  EY016150
Investigative Ophthalmology & Visual Science May 2008, Vol.49, 1341. doi:https://doi.org/
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      P. M. Geraldes, T. S. Kern, G. L. King; Activation of PKC Delta and P38 Alpha MAPK by Hyperglycemia - Novel Mechanism of Glycemic Memory in Diabetic Retinopathy. Invest. Ophthalmol. Vis. Sci. 2008;49(13):1341. doi: https://doi.org/.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: : Strict glycemic control can delay the onset of diabetic retinopathy (DR). Surprisingly, intensive glycemic therapy for many years after a period of poor glycemic control did not produce significant reduction on the progression of DR, suggesting the importance of hyperglycemia induced glycemic memory. However, this clinical observation does not yet have a clear mechanism.

Methods: : C57/BL6 background mice rendered diabetic with STZ injection for 6 months with or without insulin pellet for the last 3 months were used for histology and protein analysis. Apoptosis assessed by DNA fragmentation, DNA synthesis, in situ PKC activity and immunoblot were performed using cultured bovine retinal pericyte (BRP) stimulated with high glucose (HG) level (20mM) compared with low glucose levels (LG; 5.6 mM) for 72 hours.

Results: : Retina of diabetic mice exhibited increased pericyte loss and acellular capillaries, early and specific pathologies of DR. Similar to patients and dogs, intervention by normalized glycemic control for the last 3 months with insulin implants did not prevent pericyte loss, supporting the idea of metabolic memory. Biochemically, PKCΔ isoform and p38 MAPK activation in the retina preceded pericyte loss and were not reversed with glycemic control. Similar results on PKCΔ and p38 MAPK activation were also noted in the renal glomeruli of diabetic mice versus controls. Cultured BRP exposed to HG level for 3 days increased the rate of apoptosis by 2.2 fold (P < 0.05) and decreased DNA synthesis by 50% (P < 0.05) which did not return to basal level even when media glucose concentration was reduced to LG for 3-5 days. Biochemically, HG treatment increased PKC activity, PKCΔ isoform translocation significantly (> 2 fold) and p38 MAPK phosphorylation in parallel with elevated apoptosis, events that were not abolished by re-establishment of LG concentration. Overexpression of dominant negatives of PKCΔ or p38α MAPK isoform by adenoviral vectors both prevented and reversed HG effects to induce apoptosis in BPR.

Conclusions: : These findings have identified the activation of PKCΔ and p38α MAPK in sequence as the first novel signaling pathway by which hyperglycemia is inducing metabolic memory and apoptosis of retinal pericytes, a potential cause of DR. Inhibition of PKCΔ and p38α MAPK isoform should be considered as targets of therapies to stop the progression of DR.

Keywords: diabetic retinopathy • apoptosis/cell death • protective mechanisms 
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