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Kidney Week

Abstract: TH-PO972

Autophagy Protects Kidney Proximal Tubules from Phosphate-Mediated Mitochondrial Dysfunction

Session Information

Category: Pathology and Lab Medicine

  • 1501 Pathology and Lab Medicine: Basic

Authors

  • Fujimura, Ryuta, Osaka University Graduate School of Medicine, Osaka, Japan
  • Yamamoto, Takeshi, Osaka University Graduate School of Medicine, Osaka, Japan
  • Takabatake, Yoshitsugu, Osaka University Graduate School of Medicine, Osaka, Japan
  • Minami, Satoshi, Osaka University Graduate School of Medicine, Osaka, Japan
  • Takahashi, Atsushi, Osaka University Graduate School of Medicine, Osaka, Japan
  • Namba, Tomoko, Osaka University Graduate School of Medicine, Osaka, Japan
  • Matsuda, Jun, Osaka University Graduate School of Medicine, Osaka, Japan
  • Sakai, Shinsuke, Osaka University Graduate School of Medicine, Osaka, Japan
  • Matsui, Isao, Osaka University Graduate School of Medicine, Osaka, Japan
  • Niimura, Fumio, Tokai University School of Medicine, Isehara, KANAGAWA, Japan
  • Matsusaka, Taiji, Tokai University School of Medicine, Isehara, KANAGAWA, Japan
  • Isaka, Yoshitaka, Osaka University Graduate School of Medicine, Osaka, Japan
Background

Autophagy is one of the major degradation pathways in the cell and maintains cellular homeostasis in various settings. Hyperphosphatemia is associated with a faster progression of chronic kidney disease (CKD), as well as an increased risk of cardiovascular mortality. However, molecular mechanisms of phosphate-mediated kidney injury are largely unknown.

Methods

We investigated the pathogenesis of phosphate-mediated kidney injuries in the proximal tubular epithelial cells(PTECs) with a focus on autophagy and mitophagy, and the effects of autophagy deficiency and enhancement on kidney morphology and function during phosphate overload.

Results

In GFP-MAP1LC3 transgenic mice, high phosphate(HP) diet continuously stimulated autophagy in the PTECs. In novel mitophagy-reporter mice (mito-QC), HP diet also increased the number of mitolysosomes (mitochondria-containing autolysosomes) exclusively in the PTECs. High concentration of inorganic phosphate (Pi) in the medium increased PINK1/Parkin expression as well as autophagic activity in cultured PTECs. High Pi not only induced mitochondrial ROS production and mitochondrial permeability transition pore (mPTP) opening, but also reduced mitochondrial membrane potential, ATP production and oxygen consumption rate, all of which were significantly exaggerated by autophagy deficiency. A ROS scavenger, N-acetylcysteine (NAC), blocked mPTP opening, reduced PINK1/Parkin-dependent mitophagy, and successfully alleviated phosphate-mediated cellular damages. HP diet-fed mice showed mitochondrial dysfunction, reactive oxygen species (ROS) production, apoptosis, and inflammasome activation in the kidney, which were significantly exaggerated by autophagy deficiency. Finally, HP diet-fed proximal tubule-specific Rubicon knockout mice, in which autophagic flux is genetically enhanced, ameliorated HP-mediated kidney injuries.

Conclusion

Phosphate overload induces mitophagy in PTECs, which is indispensable for maintaining proper mitochondrial functions. Enhancing autophagic activity could be a promising way to suppress CKD progression.