Abstract: SA-PO810
ATF6α and PPARα Cross-Talk Provides New Insights into Lipotoxicity-Induced Tubulointerstitial Fibrosis
Session Information
- Molecular Mechanisms of CKD - III
October 27, 2018 | Location: Exhibit Hall, San Diego Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 1903 CKD (Non-Dialysis): Mechanisms
Authors
- Jao, Tzu-Ming, The University of Tokyo, Tokyo, Japan
- Inoue, Tsuyoshi, The University of Tokyo, Tokyo, Japan
- Sugahara, Mai, The University of Tokyo, Tokyo, Japan
- Maekawa, Hiroshi, The University of Tokyo, Tokyo, Japan
- Ishimoto, Yu, The University of Tokyo, Tokyo, Japan
- Tanaka, Tetsuhiro, The University of Tokyo, Tokyo, Japan
- Nangaku, Masaomi, The University of Tokyo, Tokyo, Japan
- Inagi, Reiko, The University of Tokyo, Tokyo, Japan
Background
Lipid accumulation in renal tubules is frequently observed in CKD patients with tubulointerstitial fibrosis (TIF). However, the molecular mechanisms modulating lipotoxicity-induced TIF remain obscure. ATF6α, a transcription factor of the unfolded protein response, is reported to be an upstream regulator of fatty acid metabolism. Fatty acids are the main energy source of proximal tubular cells (PTCs), resulting from their high energy demand. We therefore hypothesized that ATF6α regulates tubular fatty acid metabolism, and is thereby linked to lipotoxicity-induced TIF.
Methods
Human proximal tubular cells, HK-2, were transduced with Mock, dominant active ATF6α or dominant negative ATF6α lentivirus for various experiments. Kidney unilateral ischemia-reperfusion (uIRI) (27 mins) was used as a chronic kidney injury model and kidney injury was assessed on day 14 post-uIRI using WT and Atf6α-/- mice. Mitochondrial fatty acid β-oxidation, glycolysis and function were measured using a Seahorse flux analyzer.
Results
Overexpression of activated ATF6α transcriptionally downregulates PPARα, the master regulator of lipid metabolism, leading to reduced activity of fatty acid β-oxidation and cytosolic accumulation of lipid droplets in HK-2. Such ATF6α-induced lipotoxicity causes mitochondrial dysfunction, enhanced apoptosis and connective tissue growth factor (CTGF) expression, as well as reduced cell viability, suggesting the promotive effects of ATF6α in TIF. Atf6α-/- mice showed less tubular lipid accumulation in association with sustained PPARα expression after uIRI, resulting in the amelioration of apoptosis; reduced expression of CTGF, α-SMA and collagen I; and subsequent TIF. These findings indicate the pivotal role of ATF6α in lipotoxicity-mediated TIF. Administration of fenofibrate, a PPARα agonist, in uIRI-operated mice alleviated the tendency to lipid accumulation and TIF.
Conclusion
These findings indicate that under the pathogenic condition, maladaptive ATF6α activation deranges fatty acid metabolism in PTCs, which leads to lipotoxicity-mediated apoptosis and CTGF upregulation, both of which may accelerate TIF.
Funding
- Government Support - Non-U.S.