Scientists identify a possible new treatment for diabetic retinopathy

Findings reported in The American Journal of Pathology suggest that an enzymatic precursor may be toxic to retinal cells in diabetic patients


Philadelphia, September 19, 2019

About one in three diabetic patients develops diabetic retinopathy (DR), which can impair vision and lead to blindness. A new study in The American Journal of Pathology, published by Elsevier, provides clear evidence that high glucose increases the levels of enzymatic precursor—lysyl oxidase propeptide (LOX-PP)—that promotes cell death, which was verified in an animal model of diabetes. These findings may help develop novel DR treatments by targeting LOX-PP or its metabolites.

‘We found that hyperglycemic and diabetic conditions increased LOX-PP levels,” explained lead investigator Sayon Roy, PhD, of the Departments of Medicine and Ophthalmology at Boston University School of Medicine, Boston, MA, USA. “LOX-PP may induce cell death by compromising a cell survival pathway, and in retinas of diabetic rats, increased LOX-PP contributed to retinal vascular cell death associated with DR.

“Administration of recombinant LOX-PP alone was sufficient to induce cell death. This report shows novel functionality of LOX-PP in mediating cell death under high glucose condition in retinal endothelial cells as well as in diabetic animals.”

Studies in pancreatic and breast cancer cells suggest that LOX-PP overexpression may trigger cell death. The researchers therefore studied the role of LOX-PP in the retinal tissue. The retinal blood vessels of normal and diabetic rats and normal rats administered artificially synthesized LOX-PP (recombinant LOX-PP, r-LOX-PP) directly into the eye, were examined. Changes associated with DR such as swelling, blood vessel leakage, blockage or thickening of vascular walls, and histologic indicators such as acellular capillaries (AC) and pericyte loss (PL) were studied.

Series of histology slides showing the effect of recombinant lysyl oxidase propeptide (r-LOX-PP) on the development of acellular capillaries (ACs) and pericyte loss (PL) in rat retinas.
Effect of recombinant lysyl oxidase propeptide (r-LOX-PP) on the development of acellular capillaries (ACs) and pericyte loss (PL) in rat retinas. A-D: Representative retinal trypsin digest images showing retinal vascular networks of a control rat (A), diabetic (DM) rat (B), rat intravitreally injected with r-LOX-PP (C), and rat intravitreally injected with phosphate-buffered saline (PBS) (D). LOX-PP administration promoted the development of ACs (arrows) and PL (arrowheads) associated with diabetic retinopathy. Enlarged images correspond to boxed areas (Right panels of A, B, C, D). Scale bar = 100 μm.

More AC and PL were observed in the retinas of diabetic rats compared to controls. In non-diabetic rats, injection of r-LOX-PP directly into the eye also increased the number of ACs and PLs compared to rats receiving a control injection.

The effect of high glucose on retinal endothelial cells grown in culture was also studied. Adding glucose to the cell cultures up-regulated LOX-PP expression and reduced AKT (protein kinase B) activation. Cells exposed to r-LOX-PP alone exhibited increased cell death along with decreased AKT phosphorylation. The present study provides clear evidence that high glucose increases LOX-PP levels, which in turn promotes cell death. Furthermore, LOX-PP appears to induce cell death by compromising a pathway involved in cell survival.

“DR is the leading cause of blindness in the working age population,” noted Dr. Roy. “Unfortunately, there is no cure for this devastating ocular complication. Our findings suggest a novel mechanism for high glucose–induced cell death involving LOX-PP, which may be a therapeutic target in preventing retinal vascular cell loss associated with DR.”

LOX is an extracellular enzyme responsible for cross-linking collagen and elastin molecules to form a stable extracellular matrix. The role of the LOX propeptide, LOX-PP, is less understood, although it may play a role in keeping LOX in an inactive state.

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Notes for editors
The article is “Effects of High Glucose–Induced Lysyl Oxidase Propeptide on Retinal Endothelial Cell Survival: Implications for Diabetic Retinopathy,” by Dongjoon Kim, Dayeun Lee, Philip C. Trackman, and Sayon Roy (https://doi.org/10.1016/j.ajpath.2019.06.004). It will appear in The American Journal of Pathology, volume 189, Issue 10 (October 2019) published by Elsevier.

It is openly available at https://ajp.amjpathol.org/article/S0002-9440(18)30488-7/fulltext.

This work was supported by the National Institutes of Health (RO1 EY025528).

Full text of the study is available to credentialed journalists upon request; contact Eileen Leahy at +1 732 238 3628 or ajpmedia@elsevier.com. Journalists wishing to interview the authors should contact Dongjoon Kim at djkim@bu.edu or Sayon Roy at sayon@bu.edu.

About The American Journal of Pathology
The American Journal of Pathology
, official journal of the American Society for Investigative Pathology, published by Elsevier, seeks high-quality original research reports, reviews, and commentaries related to the molecular and cellular basis of disease. The editors will consider basic, translational, and clinical investigations that directly address mechanisms of pathogenesis or provide a foundation for future mechanistic inquiries. Examples of such foundational investigations include data mining, identification of biomarkers, molecular pathology, and discovery research. High priority is given to studies of human disease and relevant experimental models using molecular, cellular, and organismal approaches. ajp.amjpathol.org

About Elsevier
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