Abstract: PO0229
Decreased IFT88 Causes Cilia Shortening and Mitochondrial Dysfunction in Cisplatin-Induced Tubular Injury
Session Information
- AKI Mechanisms - 3
October 22, 2020 | Location: On-Demand
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Fujii, Rie, The University of Tokyo Graduate School of Medicine, Bunkyo-ku, Tokyo, Japan
- Inoue, Tsuyoshi, Nagasaki University School of Medicine Graduate School of Biomedical Sciences, Nagasaki, Nagasaki, Japan
- Hasegawa, Sho, The University of Tokyo Graduate School of Medicine, Bunkyo-ku, Tokyo, Japan
- Yoshioka, Kentaro, The University of Tokyo Graduate School of Medicine, Bunkyo-ku, Tokyo, Japan
- Nangaku, Masaomi, The University of Tokyo Graduate School of Medicine, Bunkyo-ku, Tokyo, Japan
- Inagi, Reiko, The University of Tokyo Graduate School of Medicine, Bunkyo-ku, Tokyo, Japan
Background
Renal primary ciilia are associated with the pathogenesis of various diseases, including acute kidney injury (AKI). The length of the primary cilia dynamically change during the progression of diseases: tubular primary cilia shortened in cisplatin-induced AKI mouse model. However, its relevance in kidney disease and the underlying mechanism are largely unknown. Tubular damage in AKI closely links to mitochondrial dysfunction. Thus, we investigated the interaction between primary cilia and mitochondria in cisplatin-induced tubular injury.
Methods
C57BL6 mice with cisplatin-induced AKI were euthanized at 72 h after disease induction to collect blood and kidney samples. In in vitro experiments, we used RPTEC/TERT1 cells, which are human proximal tubular epithelial cells that maintain the cilia length at high cell densities, and knocked down Ift88 (Ift88-KD), a cilia maintenance protein, by siRNA. Cisplatin-treated or Ift88-KD cells were assessed for the cellular phenotypic changes or mitochondrial metabolic function using the Flux Analyzer.
Results
We found that the expression of protein IFT88 was decreased in damaged tubules of cisplatin-induced AKI mice. These data were consistent with that Ift88 expression decreased in the cilia of cisplatin-treated RPTEC/TERT1 at mRNA and protein levels in association with shortening of the primary cilia, suggesting the pathogenic link between tubular damage and Ift88-mediated cilia alteration. Interestingly, Ift88-KD cells significantly exhibited shorter cilia as compared to control siRNA-transfected cells and showed downregulation of mitochondrial oxidative phosphorylation capacity and decreased ATP production, indicating the contribution of Ift88 to mitochondrial homeostasis. Of note, such mitochondrial alteration linked to tubular inflammation. Our findings suggest that tubular mitochondrial dysfunction in cisplatin-induced AKI is mediated by a decreased Ift88 with shortening cilia, at least in part.
Conclusion
Tubular mitochondrial damage followed by tubular injury in AKI may occur by the alteration of Ift88 expression, and subsequent cilia shortening in the tubular epithelial cells.