About one in three diabetes 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. More AC and PL were observed in the retinas of diabetic rats compared to
controls. In non-diabetic rats, injection of rLOX-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 rLOX-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.
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."
noted Dr. Roy.