Background: Renal tubular injury is the driving force of diabetic kidney disease (DKD) and their targeting may be an effective means for prevention. PDZK1 is a scaffold protein that is highly expressed in proximal renal tubules and participates in renal tubular reabsorption. However, the role of PDZK1 in DKD with disorder of glucose and lipid metabolism is unclear.

Methods: We generated mice lacking the Pdzk1 gene specifically in renal tubular epithelial cells by crossing Pdzk1 floxed mice with Pax8-Cre mice. We observed renal tubular injury and renal fibrosis in Pdzk1Pax8-cre+ and Pdzk1Pax8-cre- mice induced by high fat diet and streptozotin. In vitro, we elucidated that PDZK1 regulates fatty acid uptake and renal tubular injury.

Results: In this study, proteomic analysis found that compared with the control, the expression of PDZK1 in kidney of DKD mice was significantly reduced. Compared with non-DKD patients, PDZK1 was also lower in renal tissue samples of patients with DKD. Pdzk1Pax8-cre+ mice significantly increased lipid deposition of renal tubules, renal tubular injury and renal fibrosis compared with Pdzk1Pax8-cre- mice induced by high fat diet and streptozotin. Knocked down PDZK1 increased intracellular lipid deposition in renal tubular epithelial cells stimulated with high glucose and palmitic acid. Knockdown PDZK1 could promote fatty acid uptake in renal tubular epithelial cells. PDZK1 interacted with fatty acid transporter 2 (FATP2) and inhibited the expression and localization of FATP2 on cell membrane.

Conclusion: Diabetes stimulates the decreased expression of PDZK1 in renal tubular epithelial cells. The decrease of PDZK1 attenuates the inhibition of FATP2 localization on cell membrane, promoting ectopic lipid deposition and renal tubular injury, leading to DKD. This study will reveal the new regulatory mechanism of renal tubular injury and provide a new target for the treatment of DKD.

Disclosure

L. Yang: None. Y. Wang: None. Y. Xu: None. J. Ke: None. D. Zhao: None.

Funding

National Natural Science Foundation of China (82170454)

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