HDAC3 ORCHESTRATES MICROGLIAL POLARISATION AND SYNAPTIC LOSS IN THE RENAL-BRAIN AXIS: IMPLICATIONS FOR COGNITIVE DECLINE IN CKD

Histone deacetylase 3 (HDAC3) is a key regulator of epigenetic repression and microglial proliferation in CNS injury. Cognitive impairment is a debilitating hallmark of chronic kidney disease (CKD), driven by systemic inflammation and uremic toxicity. We investigated whether HDAC3 links CKD-induced neuroinflammation to cognitive decline. Hippocampal HDAC3 expression and enzymatic activity were examined in an adenine diet-induced CKD mouse model. A selective HDAC3 inhibitor (HDAC3i) was administered, and cognitive function was assessed. The microglial population were analyzed by flow cytometry, while IBA1⁺HDAC3⁺ microglia were examined in brain sections, and M1-M2 phenotypes were evaluated using RT-qPCR. Mechanistic validation was performed in vitro using N9 microglial cells exposed to control or CKD serum following HDAC3 siRNA knockdown or HDAC3i. Conditioned media from microglia were applied to N2A cells to assess neuronal health and synaptic plasticity. CKD significantly increased hippocampal HDAC3 expression and activity (reduced H3K9ac, H4K8ac) and elevated IBA1⁺HDAC3⁺ microglial populations. HDAC3i significantly improved hippocampal-dependent memory. HDAC3i reversed CKD-induced increase in MHC II⁺/CD11b⁺CD45^inter population and Nos2 and Cd38 expression, indicating attenuation of M1 polarisation. In N9 microglia, CKD serum induced increased CD68 and iNOS expression, and elevated IL-1β, TNF-α, and IL-6 levels, which were ameliorated by HDAC3i treatment. Neurons exposed to conditioned media exhibited restoration of the CREB-BDNF pathway and preservation of synaptic proteins PSD95 and synapsin-1, indicating reduced neurotoxicity. HDAC3 acts as a critical epigenetic checkpoint in the renal-brain axis, and its targeting represents a promising strategy to mitigate neuroinflammatory burden and cognitive impairment in CKD.