Alleviation of cisplatin-induced acute kidney injury using phytochemical polyphenols is accompanied by reduced accumulation of indoxyl sulfate in rats
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Polyphenols such as quercetin have been reported to prevent cisplatin-induced acute kidney injury (AKI). Indoxyl sulfate (IS), a uremic toxin generated in the liver, is increased in cisplatin AKI. The present study examined the effect of phytochemical polyphenols on serum and renal accumulations of IS in association with cisplatin AKI.
Sprague-Dawley rats were treated with cisplatin (10 mg/kg body weight) by intraperitoneal injection. Polyphenols were orally administered at −24, −1, 24 and 48 h before or after cisplatin injection. Serum levels of IS, cisplatin, serum creatinine (SCr), blood urea nitrogen (BUN) and electrolytes were measured. By using an in vitro assay system with rat liver S9 fraction, the inhibitory potencies of several compounds on IS production were determined.
Injection of cisplatin in rats markedly elevated the SCr and BUN levels, which were accompanied by tubular injuries and the expression of kidney injury molecule-1 (Kim-1). By contrast, quercetin significantly suppressed the SCr and BUN levels in the cisplatin-treated rats and protected them against renal injury with the decreased expression of Kim-1. Quercetin had no effect on serum and renal levels of cisplatin. In addition, quercetin had no effect on cisplatin-induced renal accumulation of malondialdehyde. IS concentrations in serum, kidney, liver, intestine and lung were markedly elevated by cisplatin treatment, whereas quercetin suppressed the serum and tissue IS levels. An in vitro kinetic assay revealed that quercetin displayed a potent inhibitory effect on hepatic production of IS.
Inhibition of IS accumulation by oral administration of quercetin alleviates cisplatin-induced AKI.
- Lattanzio MR, Kopyt NP. Acute kidney injury: new concepts in definition, diagnosis, pathophysiology, and treatment. J Am Osteopath Assoc. 2009;109:13–9.
- Fry AC, Farrington K. Management of acute renal failure. Postgrad Med J. 2006;82:106–16. CrossRef
- Star RA. Treatment of acute renal failure. Kidney Int. 1998;54:1817–31. CrossRef
- Taguchi T, Nazneen A, Abid MR, Razzaque MS. Cisplatin-associated nephrotoxicity and pathological events. Contrib Nephrol. 2005;148:107–21. CrossRef
- Yao X, Panichpisal K, Kurtzman N, Nugent K. Cisplatin nephrotoxicity: a review. Am J Med Sci. 2007;334:115–24. CrossRef
- Kuhlmann MK, Horsch E, Burkhardt G, Wagner M, Köhler H. Reduction of cisplatin toxicity in cultured renal tubular cells by the bioflavonoid quercetin. Arch Toxicol. 1998;72:536–40. CrossRef
- Behling EB, Sendao MC, Francescato HD, Antunes LM, Costa RS, Bianchi Mde L. Comparative study of multiple dosage of quercetin against cisplatin-induced nephrotoxicity and oxidative stress in rat kidneys. Pharmacol Rep. 2006;58:526–32.
- Do Amaral CL, Francescato HD, Coimbra TM, Costa RS, Darin JD, Antunes LM, et al. Resveratrol attenuates cisplatin-induced nephrotoxicity in rats. Arch Toxicol. 2008;82:363–70. CrossRef
- Baek SM, Kwon CH, Kim JH, Woo JS, Jung JS, Kim YK. Differential roles of hydrogen peroxide and hydroxyl radical in cisplatin-induced cell death in renal proximal tubular epithelial cells. Lab Clin Med. 2003;142:178–86. CrossRef
- Hasegawa K, Wakino S, Yoshioka K, Tatematsu S, Hara Y, Minakuchi H, et al. Kidney-specific overexpression of Sirt1 protects against acute kidney injury by retaining peroxisome function. J Biol Chem. 2010;285:13045–56. CrossRef
- Iwata K, Watanabe H, Morisaki T, Matsuzaki T, Ohmura T, Hamada A, et al. Involvement of indoxyl sulfate in renal and central nervous system toxicities during cisplatin-induced acute renal failure. Pharm Res. 2007;24:662–71. CrossRef
- Morisaki T, Matsuzaki T, Yokoo K, Kusumoto M, Iwata K, Hamada A, et al. Regulation of renal organic ion transporters in cisplatin-induced acute kidney injury and uremia in rats. Pharm Res. 2008;25:2526–33. CrossRef
- Saito H. Pathophysiological regulation of renal SLC22A organic ion transporters in acute kidney injury: pharmacological and toxicological implications. Pharmacol Ther. 2010;125:79–91. CrossRef
- Motojima M, Hosokawa A, Yamato H, Muraki T, Yoshioka T. Uraemic toxins induce proximal tubular injury via organic anion transporter 1-mediated uptake. Br J Pharmacol. 2002;135:555–63. CrossRef
- Banoglu E, Jha GG, King RS. Hepatic microsomal metabolism of indole to indoxyl, a precursor of indoxyl sulfate. Eur J Drug Metab Pharmacokinet. 2001;26:235–40.
- Banoglu E, King RS. Sulfation of indoxyl by human and rat aryl (phenol) sulfotransferases to form indoxyl sulfate. Eur J Drug Metab Pharmacokinet. 2002;27:135–40. CrossRef
- Kuhad A, Pilkhwal S, Sharma S, Tirkey N, Chopra K. Effect of curcumin on inflammation and oxidative stress in cisplatin-induced experimental nephrotoxicity. J Agric Food Chem. 2007;55:10150–5. CrossRef
- Chander V, Chopra K. Protective effect of nitric oxide pathway in resveratrol renal ischemia-reperfusion injury in rats. Arch Med Res. 2006;37:19–26. CrossRef
- Matsuzaki T, Watanabe H, Yoshitome K, Morisaki T, Hamada A, Nonoguchi H, et al. Downregulation of organic anion transporters in rat kidney under ischemia/reperfusion-induced acute renal failure. Kidney Int. 2007;71:539–47. CrossRef
- Yokoo K, Murakami R, Matsuzaki T, Yoshitome K, Hamada A, Saito H. Enhanced renal accumulation of cisplatin via renal organic cation transporter deteriorates acute kidney injury in hypomagnesemic rats. Clin Exp Nephrol. 2009;13:578–84. CrossRef
- Gelasco AK, Raymond JR. Indoxyl sulfate induces complex redox alterations in mesangial cells. Am J Physiol Renal Physiol. 2006;290:F1551–8. CrossRef
- Muteliefu G, Enomoto A, Jiang P, Takahashi M, Niwa T. Indoxyl sulphate induces oxidative stress and the expression of osteoblast-specific proteins in vascular smooth muscle cells. Nephrol Dial Transplant. 2009;24:2051–8. CrossRef
- Shimoishi K, Anraku M, Kitamura K, Tasaki Y, Taguchi K, Hashimoto M, et al. An oral adsorbent, AST-120 protects against the progression of oxidative stress by reducing the accumulation of indoxyl sulfate in the systemic circulation in renal failure. Pharm Res. 2007;24:1283–9. CrossRef
- Miyazaki T, Ise M, Seo H, Niwa T. Indoxyl sulfate increases the gene expressions of TGF-beta 1, TIMP-1 and pro-alpha 1(I) collagen in uremic rat kidneys. Kidney Int Suppl. 1997;62:S15–22.
- Miyazaki T, Ise M, Hirata M, Endo K, Ito Y, Seo H, et al. Indoxyl sulfate stimulates renal synthesis of transforming growth factor-beta 1 and progression of renal failure. Kidney Int Suppl. 1997;63:S211–4.
- Niwa T, Ise M. Indoxyl sulfate, a circulating uremic toxin, stimulates the progression of glomerular sclerosis. J Lab Clin Med. 1994;124:96–104.
- Motojima M, Hosokawa A, Yamato H, Muraki T, Yoshioka T. Uremic toxins of organic anions up-regulate PAI-1 expression by induction of NF-kappaB and free radical in proximal tubular cells. Kidney Int. 2003;63:1671–80. CrossRef
- Gillam EM, Notley LM, Cai H, De Voss JJ, Guengerich FP. Oxidation of indole by cytochrome P450 enzymes. Biochemistry. 2000;39:13817–24. CrossRef
- Zhang W, Kilicarslan T, Tyndale RF, Sellers EM. Evaluation of methoxsalen, tranylcypromine, and tryptamine as specific and selective CYP2A6 inhibitors in vitro. Drug Metab Dispos. 2001;29:897–902.
- Kharasch ED, Hankins DC, Baxter PJ, Thummel KE. Single-dose disulfiram does not inhibit CYP2A6 activity. Clin Pharmacol Ther. 1998;64:39–45. CrossRef
- Monostory K, Hazai E, Vereczkey L. Inhibition of cytochrome P450 enzymes participating in p-nitrophenol hydroxylation by drugs known as CYP2E1 inhibitors. Chem Biol Interact. 2004;147:331–40. CrossRef
- Lee SS, Buters JT, Pineau T, Fernandez-Salguero P, Gonzalez FJ. Role of CYP2E1 in the hepatotoxicity of acetaminophen. J Biol Chem. 1996;271:12063–7. CrossRef
- Wang LQ, Falany CN, James MO. Triclosan as a substrate and inhibitor of 3′-phosphoadenosine 5′-phosphosulfate-sulfotransferase and UDP-glucuronosyl transferase in human liver fractions. Drug Metab Dispos. 2004;32:1162–9. CrossRef
- Eaton EA, Walle UK, Lewis AJ, Hudson T, Wilson AA, Walle T. Flavonoids, potent inhibitors of the human P-form phenolsulfotransferase. Potential role in drug metabolism and chemoprevention. Drug Metab Dispos. 1996;24:232–7.
- Furimsky AM, Green CE, Sharp LE, Catz P, Adjei AA, Parman T, et al. Effect of resveratrol on 17beta-estradiol sulfation by human hepatic and jejunal S9 and recombinant sulfotransferase 1E1. Drug Metab Dispos. 2008;36:129–36. CrossRef
- Sato T, Miyazaki S, Mohri S. Effects of an oral adsorbent on cisplatin-induced nephropathy in rats. Nippon Jinzo Gakkai Shi. 1996;38:290–5.
- Scambia G, Ranelletti FO, Benedetti Panici P, Bonanno G, De Vincenzo R, Piantelli M, et al. Synergistic antiproliferative activity of quercetin and cisplatin on ovarian cancer cell growth. Anticancer Drugs. 1990;1:45–8. CrossRef
- Rezk YA, Balulad SS, Keller RS, Bennett JA. Use of resveratrol to improve the effectiveness of cisplatin and doxorubicin: study in human gynecologic cancer cell lines and in rodent heart. Am J Obstet Gynecol. 2006;194:e23–6. CrossRef
- Shimizu H, Hirose Y, Nishijima F, Tsubakihara Y, Miyazaki H. ROS and PDGF-beta receptors are critically involved in indoxyl sulfate actions that promote vascular smooth muscle cell proliferation and migration. Am J Physiol Cell Physiol. 2009;297:C389–96. CrossRef
- Dou L, Jourde-Chiche N, Faure V, Cerini C, Berland Y, Dignat-George F, et al. The uremic solute indoxyl sulfate induces oxidative stress in endothelial cells. J Thromb Haemost. 2007;5:1302–8. CrossRef
- Dou L, Bertrand E, Cerini C, Faure V, Sampol J, Vanholder R, et al. The uremic solutes p-cresol and indoxyl sulfate inhibit endothelial proliferation and wound repair. Kidney Int. 2004;65:442–51. CrossRef
- Faure V, Dou L, Sabatier F, Cerini C, Sampol J, Berland Y, et al. Elevation of circulating endothelial microparticles in patients with chronic renal failure. J Thromb Haemost. 2006;4:566–73. CrossRef
- Lekawanvijit S, Adrahtas A, Kelly DJ, Kompa AR, Wang BH, Krum H. Does indoxyl sulfate, a uraemic toxin, have direct effects on cardiac fibroblasts and myocytes? Eur Heart J. 2010;31:1771–9. CrossRef
- Adijiang A, Goto S, Uramoto S, Nishijima F, Niwa T. Indoxyl sulphate promotes aortic calcification with expression of osteoblast-specific proteins in hypertensive rats. Nephrol Dial Transplant. 2008;23:1892–901. CrossRef
- Taki K, Tsuruta Y, Niwa T. Indoxyl sulfate and atherosclerotic risk factors in hemodialysis patients. Am J Nephrol. 2007;27:30–5. CrossRef
- Barreto FC, Barreto DV, Liabeuf S, Meert N, Glorieux G, Temmar M, et al. Serum indoxyl sulfate is associated with vascular disease and mortality in chronic kidney disease patients. Clin J Am Soc Nephrol. 2009;4:1551–8. CrossRef
- Schepers E, Meert N, Glorieux G, Goeman J, Van der Eycken J, et al. P-cresylsulphate, the main in vivo metabolite of p-cresol, activates leucocyte free radical production. Nephrol Dial Transplant. 2007;22:592–6. CrossRef
- Liabeuf S, Barreto DV, Barreto FC, Meert N, Glorieux G, Schepers E, et al. Free p-cresylsulphate is a predictor of mortality in patients at different stages of chronic kidney disease. Nephrol Dial Transplant. 2009;25:1183–91. CrossRef
- Niwa T, Takeda N, Tatematsu A, Maeda K. Accumulation of indoxyl sulfate, an inhibitor of drug-binding, in uremic serum as demonstrated by internal-surface reversed-phase liquid chromatography. Clin Chem. 1988;34:2264–7.
- Martinez AW, Recht NS, Hostetter TH, Meyer TW. Removal of P-cresol sulfate by hemodialysis. J Am Soc Nephrol. 2005;16:3430–6. CrossRef
- Alleviation of cisplatin-induced acute kidney injury using phytochemical polyphenols is accompanied by reduced accumulation of indoxyl sulfate in rats
Clinical and Experimental Nephrology
Volume 15, Issue 6 , pp 820-830
- Cover Date
- Print ISSN
- Online ISSN
- Springer Japan
- Additional Links
- Acute kidney injury
- Indoxyl sulfate
- Uremic toxins
- Industry Sectors
- Author Affiliations
- 1. Department of Clinical Pharmaceutical Sciences, Kumamoto University Graduate School of Pharmaceutical Sciences, 5-1 Oe-honmachi, Kumamoto, 862-0973, Japan
- 3. Department of Pharmacy, Kumamoto University Hospital, 1-1-1 Honjo, Kumamoto, 860-8556, Japan
- 2. Department of Nephrology, Faculty of Life Science Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-8556, Japan