DUSP8 Ameliorates Podocyte Mitochondrial Dysfunction via PRAS40 Dephosphorylation in Diabetic Kidney Disease

Mitochondrial dysfunction is central to podocyte injury in diabetic kidney disease (DKD). Here, we observed consistent downregulation of dual-specificity phosphatase 8 (DUSP8) in glomeruli from patients with DKD, db/db mice, STZ/HFD-induced DKD mice, and high glucose-treated podocytes. Glomerular DUSP8 levels were positively correlated with the estimated glomerular filtration rate and negatively correlated with the urinary albumin-to-creatinine ratio and serum creatinine level. Functional studies demonstrated that DUSP8 alleviated high glucose-induced mitochondrial fission, reactive oxygen species accumulation, mitochondrial permeability transition pore hyperactivation, loss of mitochondrial membrane potential, and podocyte injury. In vivo, podocyte-specific DUSP8 knockout exacerbated mitochondrial dysfunction, podocyte loss, glomerular pathology, and renal functional decline in STZ/HFD-induced DKD mice. Mechanistically, DUSP8 dephosphorylated PRAS40 at Ser202 via its phosphatase activity, thereby mitigating high glucose-induced mitochondrial injury in podocytes. Consistent with these findings, podocyte-specific DUSP8 knockdown in STZ/HFD-induced DKD mice was positively correlated with PRAS40 hyperphosphorylation at Ser202, mirroring the inverse correlation between DUSP8 expression and PRAS40 phosphorylation observed in patients with DKD. Furthermore, we found that histone deacetylase 1 (HDAC1) epigenetically silenced DUSP8 transcription by deacetylating histone H3 lysine 27 (H3K27) at its promoter. Collectively, we elucidated the HDAC1/DUSP8/PRAS40 axis as a novel regulator of podocyte mitochondrial homeostasis in DKD, providing a mechanistic framework and a potential therapeutic target.