Inhibition of Plk1 Attenuates Downregulation of Water and Sodium transporters in Obstructive Nephropathy

Background: Obstructive nephropathy is frequently associated with downregulation of key renal water and sodium transporters, resulting in impaired urinary concentration and disrupted fluid balance. The present study aimed to investigate the role of Polo-like kinase 1 (Plk1), a kinase traditionally recognized for its function in cell-cycle regulation, in modulating renal water and sodium transporters in a unilateral ureteral obstruction (UUO) model, and to elucidate the underlying molecular mechanisms. Methods: Plk1 function was inhibited pharmacologically using BI6727 or genetically using heterozygous Plk1 knockout mice. In vitro, renal collecting duct M1 cells were stimulated with TGF-β to examine mechanistic pathways. Results: Inhibition of Plk1 preserved the expression of aquaporin 2 (AQP2) and Na⁺-K⁺-2Cl⁻ cotransporter type 2 (NKCC2) in UUO kidneys. Similarly, heterozygous Plk1 knockout mice exhibited higher AQP2 and NKCC2 levels than wild-type controls. Mechanistically, Plk1 regulated cytosolic phospholipase A₂ (cPLA₂) activity, leading to elevated prostaglandin E₂ (PGE₂) production. PGE₂ subsequently upregulated the E3 ubiquitin ligases NEDD4 and NEDD4L, promoting ubiquitin–proteasome–mediated degradation of AQP2 and NKCC2. Conclusion: These findings indicate that Plk1 contributes to the maladaptive downregulation of renal water and sodium transporters during obstruction. Pharmacological inhibition or genetic reduction of Plk1 preserves transporter expression, highlighting the Plk1–cPLA₂–PGE₂–NEDD4/NEDD4L axis as a potential therapeutic target for correcting water and sodium imbalance in obstructive nephropathy.