The latest research in “The American Journal of Pathology” has suggested a new possible therapy for treating diabetic nephropathy (DR). This study has also given a piece of evidence that an increase in glucose levels can enhance the levels of enzymatic precursor LOX-PP.
The research on an animal model of diabetes has proved that this lysyl oxidase propeptide (LOX-PP) plays a role in promoting cell death. Altogether, these findings are much helpful in developing new DR therapies, that target LOX-PP or its metabolites.
Increased levels of LOX-PP can trigger cell death
Almost one in three patients with diabetes have diabetic nephropathy (DR). That can worsen their vision and lead to blindness. The research team has found that there is an increase in the levels of LOX-PP during hyperglycemic and diabetic conditions.
And this enzymatic precursor can induce cell death. However, it can do so by compromising a pathway necessary for cell survival. LOX is an enzyme that is responsible for cross-linking elastin and collagen molecules to form a stable extracellular matrix.
Up till now, the function of LOX-PP (LOX propeptide), is less understood. But it may have a role in keeping LOX in its inactive form. This research has shown that in retinas of diabetic rats, high levels of lysyl oxidase propeptide have triggered retinal vascular cell death.
While further analysis has also revealed that administrating recombinant LOX-PP alone was enough to cause cell death. These findings suggest that LOX-PP plays a role in cell death under increased glucose conditions in endothelial cells of the retina as well as in diabetic animals.
Various studies in breast and pancreatic cancer cells have also found that the overexpression of LOX-PP can trigger cell death. Therefore, the research team has examined the functionality of LOX-PP in the retinal tissue.
High glucose and an increase in the expression of LOX-PP
The team observed the retinal blood vessels of diabetic and normal rats. While in some normal rats, they administered synthesized LOX-PP (rLOX-PP, recombinant LOX-PP) directly into the eye. And then examined their retinal blood vessels.
The team has also studied the changes associated with diabetic nephropathy. That may include blood vessel leakage, swelling, thickening or blockage of vascular walls, and a few histological indicators. Whereas, the histological indicators involve pericyte loss (PL) and acellular capillaries (AC).
The research team found more PL and AC in the retinas of diabetic rats in contrast to controls. While in non-diabetic rats, injecting rLOX-PP directly into the eye has also led to an increase in the number of PLs and ACs as compared to rats that received a control injection.
Later, the team analyzed the effect of high glucose levels in cultured retinal endothelial cells. And observed that adding glucose to these cell cultures has led to an upregulation in the expression of LOX-PP.
While there was a reduction in the activation of AKT (protein kinase B). Cells that were exposed to rLOX-PP alone showed an increase in cell deaths. Whereas, a notable decrease in AKT phosphorylation was also observed.
This study has provided clear evidence that increased glucose levels can lead to an increase in LOX-PP expression. In return, that will promote cell death by compromising a pathway related to cell survival.
Diabetic nephropathy is among the leading causes of blindness in the working-age population. But unfortunately, there is no cure for this complication. However, the findings of this study have suggested a new mechanism for the prevention of retinal vascular loss related to DR.