NDR2 Kinase Regulates Microglial Metabolic Adaptation and Inflammatory Response: Critical Role in Glucose-Dependent Functional Plasticity

Diabetic retinopathy (DR), a major complication of diabetes, is driven by chronic inflammation in which retinal microglial cells play a central role. The Hippo pathway kinases NDR1/2 regulate macrophage function, but their role in microglia and DR remain unknown. This study investigates the function of the NDR2 kinase in microglial cells under high-glucose (HG) conditions. Using CRISPR-Cas9, we partially knocked out the <i>Ndr2/Stk38l</i> gene in BV-2 mouse microglial cells and analyzed metabolic activity, phagocytosis, migration, and cytokine release. We confirmed NDR2 expression in microglia and observed increased levels under HG, suggesting a role in hyperglycemia-induced stress. <i>Ndr2/Stk38l</i> (<i>hereafter referred to as Ndr2</i>) downregulation impaired mitochondrial respiration and reduced metabolic flexibility, indicating defective stress adaptation. Functionally, microglia with a partial downregulation of <i>Ndr2</i> displayed reduced phagocytic and migratory capacity-both dependent on cytoskeletal dynamics. Moreover, <i>Ndr2</i> downregulation altered the secretory profile, elevating pro-inflammatory cytokines (IL-6, TNF, IL-17, IL-12p70) even under normal glucose levels. These findings identify NDR2 protein kinase as a key regulator of microglial metabolism and inflammatory behavior under diabetic conditions. By modulating immune and metabolic responses, NDR2 may contribute to the neuroinflammatory processes underlying DR. Targeting NDR2 function in microglia may offer novel therapeutic strategies to mitigate retinal inflammation and progression of DR.