Hyperglycemic stress aggravates diabetic retinopathy and nephropathy by promoting cilium disassembly via a deacetylation- and methylation-mediated regulatory mechanism
Preclinical study reveals that a PRMT1-HDAC6 feedback loop accelerates cilium loss in diabetic mice, indicating a potential therapeutic target for diabetic retinopathy and nephropathy.
Key Points
To determine the molecular mechanisms by which hyperglycemic stress promotes primary cilium disassembly and aggravates tissue injury in diabetic retinopathy and nephropathy.
Assessed ciliary structural integrity and organ function in diabetic mouse models with genetic deletion of PRMT1 or HDAC6.
Investigated the mutual post-translational modifications (arginine methylation and deacetylation) and localization of PRMT1 and HDAC6 under hyperglycemic conditions.
Administered pharmacological inhibitors targeting the PRMT1-HDAC6 regulatory axis to assess therapeutic effects on retinal and renal damage.
Hyperglycemic stress upregulated PRMT1 and HDAC6 in retinal and renal tissues, while genetic deletion of either enzyme preserved ciliary architecture and restored organ function in diabetic mice.
PRMT1 localized to the basal body and methylated HDAC6 at arginine 16 to enhance its stability, while HDAC6 deacetylated PRMT1 at lysine 128 to increase PRMT1 levels, forming a pro-disassembly positive feedback loop.
Pharmacological inhibition of the PRMT1-HDAC6 pathway significantly reduced pathological features of both diabetic retinopathy and diabetic nephropathy.