NUAK1 Promotes Diabetic Kidney Disease by Accelerating Renal Tubular Senescence via the ROS/P53 Axis

Area of Science:

• Nephrology
• Molecular Biology
• Pharmacology

Background:

• Diabetic kidney disease (DKD) pathogenesis involves complex interactions including senescence, oxidative stress, inflammation, and fibrosis.
• The precise mechanisms linking renal tubular senescence to DKD progression are not fully understood.
• NUAK1's role in DKD pathogenesis requires systematic investigation.

Purpose of the Study:

• To elucidate the regulatory role and molecular mechanisms of NUAK1 in DKD.
• To identify potential therapeutic targets and agents for DKD treatment.

Main Methods:

• Bioinformatics analysis of Gene Expression Omnibus datasets to identify differentially expressed genes.
• In vitro and in vivo studies using cell lines (HK-2), DKD mouse models, and senescent mouse models.
• NUAK1 inhibition via siRNA, pharmacological inhibitors, and adeno-associated virus (AAV)-mediated shRNA delivery.
• Chromatin immunoprecipitation quantitative PCR (ChIP-qPCR) to identify transcription factor binding.
• Molecular docking and dynamics simulations to identify potential inhibitors.
• Treatment with Asiatic acid (AA) in DKD models.

Main Results:

• NUAK1 was identified as a differentially expressed gene upregulated in DKD.
• NUAK1 inhibition attenuated renal tubular senescence, oxidative stress, inflammation, and fibrosis via the ROS/P53 axis.
• ETS1 was identified as a direct transcriptional activator of NUAK1.
• Asiatic acid (AA) was identified as a potent NUAK1 inhibitor with stable binding affinity.
• AA treatment suppressed NUAK1 expression and ameliorated renal injury in DKD models.

Conclusions:

• NUAK1 plays a critical role in DKD pathogenesis by promoting tubular senescence and oxidative stress through the ROS/P53 axis.
• ETS1 transcriptionally activates NUAK1 in DKD.
• NUAK1 is a potential therapeutic target for DKD.
• Asiatic acid (AA) represents a promising natural scaffold for developing novel NUAK1 inhibitors for DKD treatment.