Metabolic and Non-metabolic Roles of Pyruvate Kinase M2 Isoform in Diabetic Retinopathy

Krutik Soni,Raju V S Rajala,Ammaji Rajala

doi:10.1038/s41598-020-64487-2

Krutik Soni, Raju V S Rajala + Show 1 more

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https://doi.org/10.1038/s41598-020-64487-2

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Abstract

The main therapeutic goal for diabetic retinopathy (DR) is to prevent vision loss in patients with diabetes mellitus. Identifying the visual complications at a preclinical juncture will offer an early therapeutic window for diagnosis and intervention. Very recently, we found that pyruvate kinase M2 isoform (PKM2) regulates visual function through regulation of a key enzyme, phosphodiesterase 6β (Pde6β), involved in modulating photoreceptor functions. A recent study showed that the activation of PKM2 protects mitochondrial integrity in diabetic nephropathy. In the present study, we examined the role of PKM2 in DR in a mouse model that has both phenotypes of obesity and type II diabetes. In DR, we found decreased expression of PKM2 and Pde6β expression, but not PKM1. Consistent with decreased Pde6β expression, the db/db mice had reduced rod photoreceptor function. We found increased pyruvate kinase activity and a decreased ratio of reduced/oxidized redox in db/db mouse retina compared with control retinas. There was no significant difference in the levels of lactate between db/db and control mouse retina. Our findings suggest that reduced expression of PKM2 with unchanged PKM1 expression might be responsible for higher pyruvate kinase activity in db/db mouse retina. Our studies suggest that PKM2 has a role in DR. The results support that PKM2 may serve as a therapeutic target in the treatment of DR.

Highlights

Diabetic retinopathy (DR) is one of the principal causes of vision loss that stems from diabetes mellitus (DM)[1,2]
Www.nature.com/scientificreports integrity in diabetic nephropathy[13]. These studies led to the hypothesis that reduced vision loss in diabetes could be due to decreased levels of pyruvate kinase M2 (PKM2) in diabetes
Studies from our laboratory showed that the ablation of PKM2 in rod photoreceptors resulted in almost 98 percent loss of PKM2 in rod photoreceptor cells[12]

Summary

Introduction

Diabetic retinopathy (DR) is one of the principal causes of vision loss that stems from diabetes mellitus (DM)[1,2]. Several studies with diabetic animal models revealed decreased visual function[4,5]. The molecular mechanism behind this decrease is poorly understood Both rod (night vision) and cone (daylight vision) photoreceptors are highly metabolic, and their energy demand is comparable to that of rapidly growing tumor cells[6,7,8]. It was reported that PKM2 activation protects mitochondrial www.nature.com/scientificreports integrity in diabetic nephropathy[13]. These studies led to the hypothesis that reduced vision loss in diabetes could be due to decreased levels of PKM2 in diabetes. We studied the role of PKM2 in DR in a mouse model that has both phenotypes of obesity and type II diabetes

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