Mol Neurobiol. 2025 Nov 29;63(1):212. doi: 10.1007/s12035-025-05411-5.
ABSTRACT
Diabetic retinopathy (DR) is a significant complication of diabetes that results in retinal damage and the risk of blindness. Branched-chain amino acids (BCAAs) are essential amino acids that fulfill physiological roles in energy balance and neurotransmitter regulation within the retina. While high levels of BCAAs are associated with DR, their metabolism in DR remains poorly understood. This study investigated the mechanisms underlying increased BCAA levels and their role in DR using STZ-diabetic rats (4 and 8 weeks). We measured mRNA (qPCR), protein (immunoblotting/immunofluorescence), and biochemical markers (BCAA and oxidative stress). Results showed elevated BCAA levels in both the serum and the retinas of diabetic rats at 4 and 8 weeks versus controls. Large amino acid transporter (LAT1), branched-chain amino acid transferase (BCATs), and branched-chain keto dehydrogenase α subunit (BCKDE1α) mRNA levels remained significantly unchanged, while BCKDE1β subunit was notably affected by diabetes. The protein expression of BCAT1 significantly decreased in the diabetic retina after 4 and 8 weeks of diabetes. LAT1 expression increased after 8 weeks compared to 4-week diabetic rats, but this change was insignificant. The protein expression of BCAT2 and BCKDE1 subunits did not change significantly due to diabetes. Additionally, the expression levels of neurotrophic factors (BDNF), antioxidant (GSH), and glutamine synthase (GS) were lower in diabetic retinas compared to controls. In contrast, TBAR and apoptosis factors (caspase 3 and BAX) were increased in diabetic retinas. These findings suggest that increased LAT1 expression and decreased BCAT1 protein in the diabetic retina contribute to elevated BCAA levels. Together with reduced GS expression, increased oxidative stress and apoptosis may lead to neuronal damage and retinal neurodegeneration in DR, indicating the significance of altered BCAA metabolism in DR progression.
PMID:41317256 | DOI:10.1007/s12035-025-05411-5