Kidney Week

Abstract: FR-PO167

Thioredoxin-Interacting Protein (TXNIP) Regulates Mitochondrial Function and Prognosis of Ischemia/Reperfusion Induced AKI

Session Information

• Mitochondriacs and More
  November 03, 2017 | Location: Hall H, Morial Convention Center
  Abstract Time: 10:00 AM - 10:00 AM

Category: Acute Kidney Injury

• 001 AKI: Basic

Authors

• Inogtani, Satoshi, Kochi university, Nankokushi, Japan

Satoshi Inogtani,

• Hashimoto, Daisuke, Kochi university, Nankokushi, Japan

Daisuke Hashimoto,

• Ogasawara, Masami, Kochi university, Nankokushi, Japan

Masami Ogasawara,

• Eguchi, Tomohiro, Kochi university, Nankokushi, Japan

Tomohiro Eguchi,

• Nishikawa, Hirofumi, Kochi university, Nankokushi, Japan

Hirofumi Nishikawa,

• Matsumoto, Tatsuki, Kochi university, Nankokushi, Japan

Tatsuki Matsumoto,

• Ode, Kazu Hamada, Kochi university, Nankokushi, Japan

Kazu Hamada Ode,

• Shimamura, Yoshiko, Kochi Medical School,Kochi University, Nankoku, Japan

Yoshiko Shimamura,

• Inoue, Kosuke, kochi medical school, Nankoku, Japan

Kosuke Inoue,

• Taniguchi, Yoshinori, Kochi university, Nankokushi, Japan

Yoshinori Taniguchi,

• Horino, Taro, Kochi Medical School, Kochi University, Kochi, Japan

Taro Horino,

• Terada, Yoshio, None, Nankoku-city, Japan

Yoshio Terada,

Background

Thioredoxin-interacting protein (TXNIP) has been found to regulate the cellular reduction-oxidation (redox) state by binding to and inhibiting thioredoxin in a redox-dependent fashion. However, little is known about the role of TXNIP in mitochondrial function and acute kidney injury (AKI) pathogenesis.

Methods

We evaluated the role of TXNIP in renal function in bilateral renal ischemia (27 min)/reperfusion injury (IRI) model using TXNIP knock-out (KO) and wild type (WT) mice. To elucidate the functional roles of TXNIP, we evaluated mitochondrial enzymes, morphology, and NLRP3 inflammasome in primary cultured renal tubular epithelial cells (TECs).

Results

TXNIP KO mice had significantly higher SCr (0.78+0.28 versus 0.45 + 0.20 mg/dl) and significantly higher BUN (152.5+32.5 versus 75.3+18.2 mg/dl) at 24h post ischemia compared to WT mice. Immunohistological examination showed severer tubular injury in cortex and outer medulla in TXNIP KO mice. The number of TUNEL positive tubular cells and KIM-1 positive cells were increased in in TXNIP KO mice. Dysmorphic mitochondria were observed in proximal tubules of TXNIP KO mice compared to WT mice. The protein expressions of mitochondrial enzymes (ATP5a, UCP2 and complex IV) and ATP production were decreased in TXNIP KO mice at 24h post ischemia. In vitro experiments, protein and mRNA levels of ATP5a, complex IV, PGC-1a were significantly decreased by H2O2, and these reductions were more prominent in TECs of TXNIP KO mice. Moreover, NLRP3, IL-1β, and caspase 1 (p10) protein expressions were significantly increased by LPS in TECs of WT mice, but this effect was reduced in TECs of TXNIP KO mice.

Conclusion

These data demonstrate that TXNIP protects from IRI induced AKI. TXNIP regulates mitochondrial function and inflammasome in cytotoxic conditions. These results indicate that TXNIP plays a key role in the pathophysiology of AKI.