Kidney Week

Abstract: FR-PO346

ATF6 Knockout Mice Revealed That ER Stress Links Lipotoxicity and Kidney Fibrosis

Session Information

• Mechanisms Associated with Kidney Fibrosis - I
  November 03, 2017 | Location: Hall H, Morial Convention Center
  Abstract Time: 10:00 AM - 10:00 AM

Category: Chronic Kidney Disease (Non-Dialysis)

• 308 CKD: Mechanisms of Tubulointerstitial Fibrosis

Authors

• Jao, Tzu-Ming, The University of Tokyo Graduate School of Medicine, Tokyo, Japan

Tzu-Ming Jao,

• Wu, Chia-Hsien, The University of Tokyo Graduate School of Medicine, Tokyo, Japan

Chia-Hsien Wu,

• Sugahara, Mai, the University of Tokyo School of Medicine, Tokyo, Japan

Mai Sugahara,

• Saito, Hisako, the University of Tokyo School of Medicine, Tokyo, Japan

Hisako Saito,

• Ishimoto, Yu, the University of Tokyo School of Medicine, Tokyo, Japan

Yu Ishimoto,

• Okada, Akira, the University of Tokyo School of Medicine, Tokyo, Japan

Akira Okada,

• Maekawa, Hiroshi, the University of Tokyo School of Medicine, Tokyo, Japan

Hiroshi Maekawa,

• Aoe, Mari, the University of Tokyo School of Medicine, Tokyo, Japan

Mari Aoe,

• Tanaka, Tetsuhiro, the University of Tokyo School of Medicine, Tokyo, Japan

Tetsuhiro Tanaka,

• Nangaku, Masaomi, the University of Tokyo School of Medicine, Tokyo, Japan

Masaomi Nangaku,

• Inagi, Reiko, The University of Tokyo Graduate School of Medicine, Tokyo, Japan

Reiko Inagi,

Background

Lipid accumulation in tubules is frequently observed in chronic kidney disease (CKD) patients. However, the molecular mechanism underlying lipotoxicity-induced tubulointerstitial fibrosis is still largely unknown. ATF6, a transcription factor of unfolded protein response (UPR), has been reported as an upstream regulator of lipid metabolism. In addition, fatty acid is the main energy source of proximal tubular cell because of its high energy demand. We thus hypothesized that ATF6 regulates tubular lipid metabolisms, and thereby contributes to lipotoxicity-induced renal fibrosis.

Methods

We employed ATF6+/+ and ATF6-/- mice or Sprague-Dawley rats with unilateral ureteral obstruction (UUO) or unilateral ischemia-reperfusion injury (uIRI) as tubulointerstitial fibrosis models. In in vitro study, human proximal tubular cell line, HK-2, expressing active ATF6 (nATF6) was used. Change in ATF6 activation, fatty acid synthetic factors (ACC and DGAT2), b-oxidation regulators (PPARα, CPT1, CPT2 and MCAD), pro-fibrogenic factor (CTGF) were assessed.

Results

ATF6 was significantly activated in associated with tubular lipid accumulation in rat fibrotic kidneys induced by UUO and uIRI. In contrast, ATF6 deficient mice exhibited amelioration of uIRI-induced tubulointerstitial fibrosis via reduction of collagen I and a-SMA expression. Intriguingly, tubular lipid accumulation was also attenuated by ATF6 deficiency, indicating the pivotal role of ATF6 in lipotoxicity-mediated tubulointerstitial fibrosis. To reveal the molecular mechanism underlying ATF6-mediated lipotoxicity and subsequent tubulointerstitial fibrosis, we overexpressed nATF6 in HK-2 and observed that nATF6 enhances fatty acid synthetic factors, as well as downregulates b-oxidation regulators, suggesting the exacerbation effect of nATF6 in lipid accumulation. Importantly, such nATF6-induced lipotoxicity causes depleted mitochondrial respiration and ATP production, and thereby decreased cell viability, inducing apoptotic signaling and elevating CTGF expression.

Conclusion

Collectively, we unveiled the role of ATF6 in the derangement of fatty acid metabolism in the tubular cells, leading to lipotoxicity-mediated tubular apoptosis and CTGF upregulation, both of which may accelerate tubulointerstitial fibrosis.