Kidney Week

Abstract: TH-PO096

Cisplatin-Induced AKI Is Attenuated in Hepatic Sulfotransferase (Sult) 1a1-Deficient Mice by Suppressing Production of Indoxyl Sulfate (IS) and Oxidative Stress

Session Information

• AKI: Inflammation, New Technologies, Omics
  October 25, 2018 | Location: Exhibit Hall, San Diego Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

• 103 AKI: Mechanisms

Authors

• Fujino, Rika, Kumamoto University Hospital, Kumamoto, Japan

Rika Fujino,

• Matsushita, Keisuke, Kumamoto University Graduate School of Pharmaceutical Sciences , Kumamoto, Japan

Keisuke Matsushita,

• Gunda, Nao, Kumamoto University Graduate School of Pharmaceutical Sciences , Kumamoto, Japan

Nao Gunda,

• Jono, Hirofumi, Kumamoto University Hospital, Kumamoto, Japan

Hirofumi Jono,

• Saito, Hideyuki, Kumamoto University Hospital, Kumamoto, Japan

Hideyuki Saito,

Background

The toxicological process leading to cisplatin-induced AKI is caused by several mechanisms, including inflammatory responses, oxidative stress and apoptosis in renal tubules. We have reported that IS, a sulfate-conjugated uremic solute, accumulates extensively in serum and kidney of animal models of cisplatin AKI. IS is derived from the liver through metabolic process by hepatic CYP2A6/2E1 and Sult1a1, however, pathophysiological role of Sult1a1 in cisplatin AKI has not been elucidated. We generated the Sult1a1 gene-deficient mice (Sult1a1^-/-), and evaluated the toxico-pharmacological role of IS in cisplatin AKI.

Methods

C57BL/6 mice (WT) and Sult1a1^-/- were treated with cisplatin (20 mg/kg) by intraperitoneal injection. In additional experiments, Sult1a1^-/- were treated with IS after cisplatin administration. Gene expression of Sult1a1 and other Sult species were determined by qRT-PCR. IS and indoxyl-β-D-glucuronide (IG) levels were determined by LC-MS/MS. Accumulation of IS and 4-hydroxy-2-nonenal (4-HNE), an oxidative stress marker, in renal tissue were examined immunohistochemically. BUN, serum creatinine, Kim-1 and Ngal were determined. Cisplatin concentration in serum and kidney was measured as the ¹⁹⁴Pt levels using ICP-MS.

Results

Sult1a1 mRNA expression was not detected in the liver of Sult1a1^-/-, and was significantly elevated (5.9-fold) in WT liver with cisplatin AKI, whereas mRNA expression of other Sult gene family members were not significantly differed between WT and Sult1a1^-/- after cisplatin treatment. In cisplatin-treated Sult1a1^-/-, kidney injury markers, renal IS level and 4-HNE accumulation were markedly reduced compared with those in WT kidney. IG concentrations in serum and kidney were elevated in cisplatin-treated Sult1a1^-/-, suggesting that glucuronidation serves as an alternative detoxification pathway for indoxyl. Administration of IS to cisplatin-treated Sult1a1^-/- reproduced severe AKI as observed in WT. Renal accumulation of ¹⁹⁴Pt showed no significant difference between Sult1a1^-/- and WT.

Conclusion

IS could be one of exacerbation factors in cisplatin AKI by accelerating oxidative stress. Hepatic Sult1a1 was the enzyme responsible for deriving IS, suggesting a potent preventive target for cisplatin nephropathy.

Funding

• Government Support - Non-U.S.