Abstract: TH-PO307
Experimental Confirmation of the Toxico-Pharmacological Role of Sulfate-Conjugated Uremic Solutes in Cisplatin Nephropathy
Session Information
- AKI Basic: Oxidative Injury and Nephrotoxins
November 02, 2017 | Location: Hall H, Morial Convention Center
Abstract Time: 10:00 AM - 10:00 AM
Category: Acute Kidney Injury
- 001 AKI: Basic
Authors
- Fujino, Rika, Kumamoto University Hospital, Kumamoto, Japan
- Unoki, Shohei, Kumamoto University Graduate School of Pharmaceutical Sciences , Kumamoto, Japan
- Tanaka, Hitomi, Kumamoto University Graduate School of Pharmaceutical Sciences , Kumamoto, Japan
- Matsushita, Keisuke, Kumamoto University Graduate School of Pharmaceutical Sciences , Kumamoto, Japan
- Yoneda, Go, Kumamoto University Graduate School of Pharmaceutical Sciences , Kumamoto, Japan
- Miyake, Shunsuke, Kumamoto University Graduate School of Pharmaceutical Sciences , Kumamoto, Japan
- Jono, Hirofumi, Kumamoto University Hospital, Kumamoto, Japan
- Saito, Hideyuki, Kumamoto University Hospital, Kumamoto, Japan
Background
The toxicological process leading to cisplatin-induced nephropathy is known to be caused by several mechanisms, including inflammatory responses, oxidative stress, DNA damage and apoptosis in renal tubules. We have reported that indoxyl sulfate (IS), a typical uremic toxin generated by hepatic sulfotransferase-mediated sulfation of indoxyl, accumulates markedly in serum and several tissues of animal models with cisplatin-induced acute kidney injury (AKI). AST-120, an orally administered spherical carbon adsorbent, suppressed the renal IS accumulation in association with a significant nephropreventive effect. The present study was aimed to confirm the toxico-pharmacological role of sulfate-conjugated uremic solutes, IS and p-cresylsulfate (PCS), in cisplatin-induced AKI models.
Methods
SD rats or C57BL/6 mice were treated with cisplatin (20 mg/kg body weight) by intraperitoneal injection. Serum and tissues were collected periodically after cisplatin administration. IS and PCS levels in serum and tissues were determined by LC-MS. Accumulation of IS and 4-Hydroxy-2-nonenal (4-HNE), an oxidative stress marker, in renal tissue was examined by immunohistochemical method.
Results
We developed an in vitro screening system for exploring inhibitors of hepatic production of IS. By using the screening system, we found that some compounds had a potent inhibitory effect on hepatic IS production. Administration of these compounds to rats with cisplatin-induced AKI ameliorated the disturbed renal function with the suppression of serum and tissue IS levels. In C57BL/6 wild type (WT) mice and sulfotransferase 1A1 gene-deficient mice (Sult1A1-/-) treated with cisplatin, renal function was preserved (BUN, 193.5 mg/dl in WT vs 84.7 mg/dl in Sult1A1-/-, p<0.01; sCr, 1.40 mg/dl in WT vs 0.42 mg/dl in Sult1A1-/-, p<0.01) in association with the marked suppression of serum IS and PCS levels (IS, 88.3 μM in WT vs 20.0 μM in Sult1A1-/-, p<0.001; PCS, 41.0 μM in WT vs 0.1 μM in Sult1A1-/-, p<0.01). Renal accumulation of IS, PCS and 4-HNE were markedly reduced in Sult1A1-/- compared with those in WT.
Conclusion
IS and PCS appeared to be key progression factors in cisplatin-induced AKI via producing oxidative stress, suggesting that hepatic Sult1A1 could be a therapeutic target for cisplatin nephropathy.
Funding
- Government Support - Non-U.S.