Abstract: SA-PO742
Unilateral Ureter Obstruction (UUO)-Induced Renal Fibrosis Is Attenuated by Suppression of Indoxyl Sulfate (IS) Accumulation in Sulfotransferase (Sult)1a1-Deficient Mice
Session Information
- CKD: Mechanisms - III
November 09, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2103 CKD (Non-Dialysis): Mechanisms
Authors
- Huixian, Hou, Kumamoto University Graduate School of Pharmaceutical Sciences, Kumamoto, Japan
- Fujino, Rika, Kumamoto University Hospital, Kumamoto, Japan
- Hayashi, Yuya, Kumamoto University Hospital, Kumamoto, Japan
- Unoki, Jumpei, Kumamoto University Graduate School of Pharmaceutical Sciences, Kumamoto, Japan
- Matsushita, Keisuke, Kumamoto University Graduate School of Pharmaceutical Sciences, Kumamoto, Japan
- Gunda, Nao, Kumamoto University Graduate School of Pharmaceutical Sciences, Kumamoto, Japan
- Jono, Hirofumi, Kumamoto University Hospital, Kumamoto, Japan
- Saito, Hideyuki, Kumamoto University Hospital, Kumamoto, Japan
Background
Obstructive nephropathy is the result of functional or anatomic lesions located in the urinary tract, and renal interstitial fibrosis is a common finding associated with long-term nephropathy. Many factors are involved in the pathogenesis of renal fibrosis, such as macrophages, growth factors, oxidative stress and inflammatory cytokines. Indoxyl sulfate (IS), a typical sulfate-conjugated uremic solute, accumulates markedly in serum and kidney of drug or ischemic AKI models, thereby inducing oxidative stress. IS is produced predominantly in the liver by CYP2A6/2E1-mediated oxidative metabolism of gut microflora-derived indole to indoxyl, followed by Sult1a1-mediated sulfate transfer to indoxyl. Thus, we established Sult1a1 gene-deficient (KO) mice to investigate the pathological role of IS in UUO-induced renal interstitial fibrosis.
Methods
The left ureter of C57BL/6J mice (wide type, WT, 8wks-old) and KO (8wks-old) were obstructed last for 2 weeks. IS concentration in serum and renal tissue was determined by LC-MS/MS. BUN was determined as renal damage marker. Changes in interstitial fibrosis formation was histologically examined by Sirius red staining. Renal fibrosis-related factors（Col1a1, α-SMA，TGF-β1）were detected by Western blot analysis or quantitative qRT-PCR.
Results
Elevated BUN in WT-UUO mice was significantly reduced in KO-UUO mice (1.44-fold). By UUO treatment, IS accumulation in serum, kidney and liver were markedly elevated in WT-UUO mice, which were suppressed in KO-UUO mice. IS accumulation in the unobstructed kidney was also decreased in KO-UUO mice. Remarkable interstitial fibrosis was observed in the kidney of WT-UUO, but was partly prevented in the kidney of KO-UUO mice. The medulla portion in the kidney of KO-UUO mice exhibited alleviated atrophy compared with that in WT-UUO mice. The high expression of Col1a1, α-SMA and TGF-β1 in the kidney of WT-UUO was suppressed in KO-UUO mice, 1.40-fold, 2.30-fold and 1.68-fold, respectively.
Conclusion
Sult1a1-deficient mice showed suppressed IS accumulation in the serum and kidney after UUO treatment, suggesting that Sult1a1 is the enzyme responsible for IS production. Renal IS accumulation during progression of UUO nephropathy could enhance interstitial fibrosis.