Reduction of PDZK1 promotes diabetic kidney disease by modulating fatty acid uptake in proximal tubular epithelial cells.

INTRODUCTION

Renal tubular injury drives the progression of diabetic kidney disease (DKD) and represents a promising therapeutic target. PDZK1, a scaffolding protein highly expressed in proximal tubules, regulates tubular reabsorption; however, its role in the metabolic dysregulation underlying DKD remains unclear. This study aimed to investigate the contribution of PDZK1 to metabolic dysfunction during DKD progression.

METHODS

We induced DKD in C57BL/6 J mice using a high-fat diet (HFD) combined with streptozotocin (STZ). Quantitative proteomic analysis of the renal cortex revealed marked downregulation of PDZK1, which was subsequently confirmed in both murine DKD models and human DKD patients. To assess PDZK1 function, we generated global PDZK1 knockout mice and conditional knockout mice (Pdzk1Pax8-cre+).

RESULTS

Following HFD/STZ challenge, mice exhibited exacerbated tubular lipid accumulation, tubular injury, and interstitial fibrosis compared with controls. PDZK1 silencing enhanced fatty acid uptake and lipid accumulation under high-glucose/palmitate stress, whereas PDZK1 overexpression mitigated these effects. Mechanistically, PDZK1 directly interacted with fatty acid transport protein 2 (FATP2) and restricted its localization to the plasma membrane. Loss of PDZK1 enabled FATP2 translocation to the membrane, thereby increasing fatty acid influx and promoting lipotoxic tubular damage. Restoration of endogenous PDZK1 or pharmacological inhibition of FATP2 attenuated DKD progression.

CONCLUSION

Collectively, diabetes-associated PDZK1 deficiency disrupts the PDZK1-FATP2 axis, leading to enhanced FATP2 membrane anchoring, ectopic lipid deposition, and tubular injury.