title: Hepatic sulfotransferase as a nephropreventing target by suppression of the uremic toxin indoxyl sulfate accumulation in ischemic acute kidney injury.
abstract: Ischemia/reperfusion (I/R)-induced acute kidney injury (AKI) is evoked by diverse pathophysiological conditions and/or surgical procedures. Here, we evaluated the nephropreventive effect of sulfotransferase (SULT) inhibitors, quercetin, and resveratrol, which hamper hepatic indoxyl sulfate (IS) production. I/R of the kidney caused severe renal injury with marked accumulation of serum and renal IS and urinary excretion of kidney injury molecule-1. Oral administration of AST-120 resulted in a significant restoration of kidney injury, suggesting that uremic toxins, which can be suppressed or adsorbed by AST-120 in the intestine, contribute to the progression or development of I/R-induced AKI. Oral administration of resveratrol or quercetin, SULT inhibitors, suppressed IS accumulation, accompanied by significant amelioration of renal dysfunction. The expression of nuclear factor E2-related factor 2 (Nrf2) in the renal nuclear fractions was markedly elevated by renal I/R, but suppressed by treatment with SULT inhibitors. IS is primarily taken up by HK-2 cells derived from human proximal tubular cells via organic anion transporters, which then evokes activation of Nrf2, most likely due to intracellular oxidative stress. Renal basolateral organic anion transporters OAT1 and OAT3, which mediate renal tubular uptake of IS in basolateral membrane, were markedly downregulated by renal I/R, but restored by SULT inhibitors. Our results suggest that renal accumulation of IS in ischemic AKI induces oxidative stress and downregulation of organic anion transporters resulting in kidney damage, which could be restored to some extent by inhibiting hepatic SULT activity as a nephropreventive target.
authors: Department of Pharmacy, Kumamoto University Hospital, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan Department of Clinical Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan saitohide@fc.kuh.kumamoto-u.ac.jp.
authors: Hideyuki
authors: H
authors: Saito
authors: Department of Clinical Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
authors: Misato
authors: M
authors: Yoshimura
authors: Department of Clinical Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
authors: Chika
authors: C
authors: Saigo
authors: Department of Clinical Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
authors: Megumi
authors: M
authors: Komori
authors: Department of Clinical Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
authors: Yui
authors: Y
authors: Nomura
authors: Department of Clinical Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
authors: Yuko
authors: Y
authors: Yamamoto
authors: Department of Clinical Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
authors: Masataka
authors: M
authors: Sagata
authors: Department of Clinical Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
authors: Ayaka
authors: A
authors: Wakida
authors: Department of Clinical Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
authors: Erina
authors: E
authors: Chuman
authors: Department of Hemo-Dialysis, Kumamoto University Hospital, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan.
authors: Kazuhiko
authors: K
authors: Nishi
authors: Department of Pharmacy, Kumamoto University Hospital, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan Department of Clinical Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
authors: Hirofumi
authors: H
authors: Jono
mesh_terms: D058186:Acute Kidney Injury / Q000378:metabolism / Q000517:prevention & control* / Q000652:urine; D000818:Animals; D015153:Blotting, Western; D002244:Carbon / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D007200:Indican / Q000097:blood / Q000652:urine*; D017879:Isothiocyanates / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D010087:Oxides / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D011794:Quercetin / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000378:metabolism / Q000517:prevention & control* / Q000652:urine; D000077185:Resveratrol; D013267:Stilbenes / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D015238:Sulfotransferases / Q000037:antagonists & inhibitors*; D013454:Sulfoxides
chemical_list: D004791:Enzyme Inhibitors; D017879:Isothiocyanates; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D010087:Oxides; D013267:Stilbenes; D013454:Sulfoxides; D002244:Carbon; C040896:AST 120; D011794:Quercetin; D015238:Sulfotransferases; C016766:sulforaphane; D007200:Indican; D000077185:Resveratrol
keywords: Nrf2; acute kidney injury; indoxyl sulfate; phytochemical polyphenols; sulfotransferase