Abstract: SA-PO129
Ischemia-Reperfusion-Induced AKI (IR-AKI) Associated with Renal Fibrosis Is Attenuated Through Suppressing Indoxyl Sulfate Accumulation in Sulfotransferase (Sult) 1a1-Deficient Mice
Session Information
- AKI: Mechanisms - AKI-CKD Transition
November 09, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Matsushita, Keisuke, Kumamoto University Graduate School of Pharmaceutical Sciences, Kumamoto, Japan
- Gunda, Nao, Kumamoto University Graduate School of Pharmaceutical Sciences, Kumamoto, Japan
- Fujino, Rika, Kumamoto University Hospital, Kumamoto, Japan
- Nishigaki, Aina, Kumamoto University Graduate School of Pharmaceutical Sciences, Kumamoto, Japan
- Hayashi, Yuya, Kumamoto University Hospital, Kumamoto, Japan
- Nishi, Kazuhiko, Kumamoto University Hospital, Kumamoto, Japan
- Jono, Hirofumi, Kumamoto University Hospital, Kumamoto, Japan
- Saito, Hideyuki, Kumamoto University Hospital, Kumamoto, Japan
Background
IR-AKI is a high risk factor in the progression towards chronic kidney disease (CKD), which is featured by renal fibrosis. Indoxyl sulfate (IS), a typical uremic solute, is accumulated in the various organs of CKD patients, whereas the relationship of IS levels and AKI-to-CKD transition associated with renal fibrosis has not been clarified. 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. We established the Sult1a1 gene-deficient mice (Sult1a1-/-), and explored the toxicological roles of IS in IR-induced AKI-to-CKD process associated with renal fibrosis.
Methods
C57BL/6 mice (WT) and Sult1a1-/- (9wks) were subjected to 30 min of renal IR, and sacrificed at 28 days after surgery. Serum creatinine (sCr) and BUN were evaluated as renal function markers. IS accumulation in serum and renal tissue was determined by LC-MS/MS. Renal fibrosis was assessed by Sirius red staining, and mRNA expression of fibrosis-related genes including Col1a1 and PAI-1 were determined by qRT-PCR.
Results
Sult1a1-/- mice subjected to IR showed partial prevention of renal damage compared to WT mice with IR treatment: sCr, 0.80 mg/dl in WT vs 0.33 mg/dl in Sult1a1-/-, p<0.01; BUN, 75.0 mg/dl in WT vs 45.8 mg/dl in Sult1a1-/-. Renal dysfunction was associated with the suppression of serum and renal tissue IS levels in Sult1a1-/- mice: serum, 23.1 μM in WT vs 1.8 μM in Sult1a1-/, p<0.01; renal tissue, 15.0 nmol/g tissue in WT vs 0.06 nmol/g tissue in Sult1a1-/-, p<0.01). IR treatment caused marked renal interstitial fibrosis in both WT and Sult1a1-/- mice, whereas fibrosis formation in the cortex of the kidney showed a tendency to be reduced in Sult1a1-/- mice, compared to WT mice. mRNA expression of Col1a1 and PAI-1 in the kidney were markedly increased in both WT and Sult1a1-/- mice treated with IR, however, these gene levels were suppressed in Sult1a1-/- mice compared with WT mice.
Conclusion
Sult1a1 appeared to be the key hepatic enzyme responsible for deriving IS in IR-AKI. IS could be one of the exacerbation factors in IR-induced AKI-to-CKD transition by promoting renal fibrosis.