[en] Context: Acute kidney injury (AKI) is often encountered in patients receiving cisplatin (CisPt), a chemotherapeutic drug that induces numerous toxic side effects. Techniques used to limit nephrotoxicity during CisPt treatment are not fully effective; about a third of patients experience AKI. New nephroprotective strategies, including pharmacological approaches, must be developed. Objective: The present study investigated the nephroprotective potential of Angelica sinensis (Oliv.) Diels (Apiaceae) root towards CisPt tubulotoxicity. Materials and methods: HK-2 cells were incubated with CisPt (10 mM) and/or with a methanolic extract of A. sinensis (AS). Nephroprotective capacity was evaluated by means of cellular viability (resazurin assay) and apoptosis (annexin-V/PI staining), oxidative stress generation (H2DCF-DA oxidation), Ki-67 index (immunofluorescence), cell cycle analysis (DNA staining), cell migration rate (scratch assay), extracellular matrix deposition (collagen determination), and b-catenin relocalization. Results: CisPt decreased cell viability [76% versus Ctrl], which was associated with an increased apoptosis. Simultaneous treatment with 50 mg/ml AS enhanced cell survival [84% versus Ctrl] and decreased the apoptosis rate. AS could not alleviate CisPt-induced oxidative stress; but doses of 5 and 50 mg/ml raised the Ki-67 index [135 and 244% versus Ctrl] and cell migration rates [1.2 and 1.3-fold versus Ctrl]. Finally, both doses of AS limited the amount of collagen deposition [121.6 and 119.6% for 5 and 50 mg/ml, respectively, versus 131.0% for CisPt-treated cells] and prevented the relocalization of b-catenin from the membrane to the nucleus. Conclusion: These results confirm the nephroprotective potential of A. sinensis and require further investigations aiming at identifying its active compounds.
Anonymous. (2011). FlowJo, data analysis software for flow cytometry. In: FlowJo Advanced Tutorial. 7.6.2 ed. Ashland: Tree Star Inc.
Barabas K, Milner R, Lurie D, Adin C. (2008). Cisplatin: A review of toxicities and therapeutic applications. Vet Comp Oncol 6:1-18.
Bozic M, De Rooij J, Parisi E, et al. (2011). Glutamatergic signaling maintains the epithelial phenotype of proximal tubular cells. J Am Soc Nephrol 22:1099-111.
Bucaloiu ID, Kirchner HL, Norfolk ER, et al. (2012). Increased risk of death and de novo chronic kidney disease following reversible acute kidney injury. Kidney Int 81:477-85.
Bunel V, Antoine MH, Nortier J, et al. (2014). Protective effects of schizandrin and schizandrin B towards cisplatin nephrotoxicity in vitro. J Appl Toxicol 34:1311-19.
Chao WW, Lin BF. (2011). Bioactivities of major constituents isolated from Angelica sinensis (Danggui). Chin Med 6:1-7.
Choy YM, Leung KN, Cho CS, et al. (1994). Immunopharmacological studies of low molecular weight polysaccharide from Angelica sinensis. Am J Chin Med 22:137-45.
Council of Europe. (2013). European Pharmacopoeia. Strasbourg: Tec & Doc.
Docherty NG, O'Sullivan OE, Healy DA, et al. (2006). TGF-beta1-induced EMT can occur independently of its proapoptotic effects and is aided by EGF receptor activation. Am J Physiol Renal Physiol 290: F1202-12.
Dos Santos NA, Carvalho Rodrigues MA, Martins NM, Dos Santos AC. (2012). Cisplatin-induced nephrotoxicity and targets of nephroprotection: An update. Arch Toxicol 86:1233-50.
Geback T, Schulz MM, Koumoutsakos P, Detmar M. (2009). TScratch: A novel and simple software tool for automated analysis of monolayer wound healing assays. Biotechniques 46:265-74.
Gottardi CJ, Gumbiner BM. (2004). Distinct molecular forms of betacatenin are targeted to adhesive or transcriptional complexes. J Cell Biol 167:339-49.
Hao S, He W, Li Y, et al. (2011). Targeted inhibition of b-catenin/CBP signaling ameliorates renal interstitial fibrosis. J Am Soc Nephrol 22: 1642-53.
Havasi A, Borkan SC. (2011). Apoptosis and acute kidney injury. Kidney Int 80:29-40.
He W, Kang YS, Dai C, Liu Y. (2011). Blockade of Wnt/beta-catenin signaling by paricalcitol ameliorates proteinuria and kidney injury. J Am Soc Nephrol 22:90-103.
Hsiao CY, Hung CY, Tsai TH, Chak KF. (2012). A study of the wound healing mechanism of a Traditional Chinese Medicine, Angelica sinensis, using a proteomic approach. Evid Based Complement Alternat Med 2012:467531.
Hu Q, Noor M, Wong YF, et al. (2009). In vitro anti-fibrotic activities of herbal compounds and herbs. Nephrol Dial Transpl 24:3033-41.
Jamieson ER, Lippard SJ. (1999). Structure, recognition, and processing of cisplatin-DNA adducts. Chem Rev 99:2467-98.
Lee SB, Kalluri R. (2010). Mechanistic connection between inflammation and fibrosis. Kidney Int 78:S22-6.
Li X, Wang H. (2005). Chinese herbal medicine in the treatment of chronic kidney disease. Adv Chronic Kidney Dis 12:276-81.
Lieberthal W, Triaca V, Levine J. (1996). Mechanisms of death induced by cisplatin in proximal tubular epithelial cells: Apoptosis vs. necrosis. Am J Physiol 270:F700-8.
Lin B. (2011). Polyphenols and neuroprotection against ischemia and neurodegeneration. Mini Rev Med Chem 11:1222-38.
Liu Y. (2006). Renal fibrosis: New insights into the pathogenesis and therapeutics. Kidney Int 69:213-17.
Liu Y. (2010). New insights into epithelial-mesenchymal transition in kidney fibrosis. J Am Soc Nephrol 21:212-22.
Low Dog T. (2005). Menopause: A review of botanical dietary supplements. Am J Med 118:98-108.
Megyesi J, Andrade L, Vieira Jr JM, et al. (2002). Coordination of the cell cycle is an important determinant of the syndrome of acute renal failure. Am J Physiol Renal Physiol 283:F810-16.
Meng LQ, Tang JW, Wang Y, et al. (2011). Astragaloside IV synergizes with ferulic acid to inhibit renal tubulointerstitial fibrosis in rats with obstructive nephropathy. Br J Pharmacol 162:1805-18.
Nagwani S, Tripathi YB. (2010). Amelioration of cisplatin induced nephrotoxicity by PTY: A herbal preparation. Food Chem Toxicol 48: 2253-8.
Nitha B, Janardhanan KK. (2008). Aqueous-ethanolic extract of morel mushroom mycelium Morchella esculenta, protects cisplatin and gentamicin induced nephrotoxicity in mice. Food Chem Toxicol 46: 3193-9.
Pabla N, Dong Z. (2008). Cisplatin nephrotoxicity: Mechanisms and renoprotective strategies. Kidney Int 73:994-1007.
Pozdzik AA, Salmon IJ, Debelle FD, et al. (2008). Aristolochic acid induces proximal tubule apoptosis and epithelial to mesenchymal transformation. Kidney Int 73:595-607.
Ruszymah BH, Chowdhury SR, Manan NA, et al. (2012). Aqueous extract of Centella asiatica promotes corneal epithelium wound healing in vitro. J Ethnopharmacol 140:333-8.
Ryan MJ, Johnson G, Kirk J, et al. (1994). HK-2: An immortalized proximal tubule epithelial cell line from normal adult human kidney. Kidney Int 45:48-57.
Sohn SH, Lee H, Nam JY, et al. (2009). Screening of herbal medicines for the recovery of cisplatin-induced nephrotoxicity. Environ Toxicol Pharmacol 28:206-12.
Urruticoechea A, Smith IE, Dowsett M. (2005). Proliferation marker Ki-67 in early breast cancer. J Clin Oncol 23:7212-20.
Valcu M, Valcu CM. (2011). Data transformation practices in biomedical sciences. Nat Methods 8:104-5.
Wang H, Li J, Yu L, et al. (2004). Antifibrotic effect of the Chinese herbs, Astragalus mongholicus and Angelica sinensis, in a rat model of chronic puromycin aminonucleoside nephrosis. Life Sci 74:1645-58.
WHO. ( 2004). WHO Monographs on Selected Medicinal Plants. Geneva: World Health Organization.
Wojcikowski K, Wohlmuth H, Johnson DW, et al. (2009). An in vitro investigation of herbs traditionally used for kidney and urinary system disorders: Potential therapeutic and toxic effects. Nephrology 14:70-9.
Wynn TA. (2007). Common and unique mechanisms regulate fibrosis in various fibroproliferative diseases. J Clin Invest 117:524-9.
Wynn TA. (2010). Fibrosis under arrest. Nat Med 16:523-5.
Xu Q, Norman JT, Shrivastav S, et al. (2007). In vitro models of TGF-beta-induced fibrosis suitable for high-throughput screening of antifibrotic agents. Am J Physiol Renal Physiol 293:F631-40.
Yan R, Ko NL, Li SL, et al. (2008). Pharmacokinetics and metabolism of ligustilide, a major bioactive component in Rhizoma Chuanxiong, in the rat. Drug Metab Dispos 36:400-8.
Yang L, Besschetnova TY, Brooks CR, et al. (2010). Epithelial cell cycle arrest in G2/M mediates kidney fibrosis after injury. Nat Med 16: 535-43. 1 p following 143.
Yang WJ, Li DP, Li JK, et al. (2009). Synergistic antioxidant activities of eight traditional Chinese herb pairs. Biol Pharm Bull 32:1021-6.
Yao X, Panichpisal K, Kurtzman N, Nugent K. (2007). Cisplatin nephrotoxicity: A review. Am J Med Sci 334:115-24.
Ye YN, Koo MW, Li Y, et al. (2001). Angelica sinensis modulates migration and proliferation of gastric epithelial cells. Life Sci 68: 961-8.
Yu F, Li H, Meng Y, Yang D. (2013). Extraction optimization of Angelica sinensis polysaccharides and its antioxidant activity in vivo. Carbohydr Polym 94:114-19.
Zeisberg M, Duffield JS. (2010). Resolved: EMT produces fibroblasts in the kidney. J Am Soc Nephrol 21:1247-53.
Zeisberg M, Neilson EG. (2009). Biomarkers for epithelial-mesenchymal transitions. J Clin Invest 119:1429-37.