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Cell Biology and Toxicology

, Volume 31, Issue 6, pp 285–293 | Cite as

Human kidney proximal tubule cells are vulnerable to the effects of Rauwolfia serpentina

  • Miriam E. MossobaEmail author
  • Thomas J. Flynn
  • Sanah Vohra
  • Paddy L. Wiesenfeld
  • Robert L. Sprando
Original Article

Abstract

Rauwolfia serpentina (or Snake root plant) is a botanical dietary supplement marketed in the USA for maintaining blood pressure. Very few studies have addressed the safety of this herb, despite its wide availability to consumers. Its reported pleiotropic effects underscore the necessity for evaluating its safety. We used a human kidney cell line to investigate the possible negative effects of R. serpentina on the renal system in vitro, with a specific focus on the renal proximal tubules. We evaluated cellular and mitochondrial toxicity, along with a variety of other kidney-specific toxicology biomarkers. We found that R. serpentina was capable of producing highly detrimental effects in our in vitro renal cell system. These results suggest more studies are needed to investigate the safety of this dietary supplement in both kidney and other target organ systems.

Keywords

Kidney proximal tubule Rauwolfia serpentina Nephrotoxicity HK-2 

Abbreviations

ROS

Reactive oxygen species

MMP

Mitochondrial membrane potential

KIM-1

Kidney injury molecule-1

B2M

Beta-2-microglobulin

Notes

Acknowledgments

We thank Dr. Vijayasankar Raman and Dr. Ikhlas Khan at the University of Mississippi NCNPR for their contributions in authenticating and providing R. serpentina material.

References

  1. Abdel-Rahman A, Anyangwe N, Carlacci L, Casper S, Danam RP, Enongene E, et al. The safety and regulation of natural products used as foods and food ingredients. Toxicol Sci. 2011;123:333–48. doi: 10.1093/toxsci/kfr198.CrossRefPubMedGoogle Scholar
  2. Achor RP, Hanson NO, Gifford Jr RW. Hypertension treated with Rauwolfia serpentina (whole root) and with reserpine: controlled study disclosing occasional severe depression. J Am Med Assoc. 1955;159:841–5. doi: 10.1001/jama.1955.02960260011004.CrossRefPubMedGoogle Scholar
  3. Armstrong B, White G, Skegg D, Doll. R, Rauwolfia derivatives and breast cancer in hypertensive women. Lancet. 1976;Originally published as Volume 2, Issue 7975 308, 8–12. doi:  10.1016/S0140-6736(76)92966-4
  4. ars-grin.gov. USDA Agricultural Research Service ARS: Chemicals in Rauvolfia serpentina (L.) BENTH. ex KURZ (apocynaceae), Dr. Duke’s Phytochemical and Ethnobotanical Databases [WWW Document URL http://www.ars-grin.gov/cgi-bin/duke/farmacy2.pl];(2015) Accessed 11 Feb 2015.
  5. Azmi MB, Qureshi SA. Methanolic root extract of Rauwolfia serpentina improves the glucose tolerance in Wister mice. Adv Pharmacol Sci. 2012. doi: 10.6227/jfda.2012200208.PubMedCentralPubMedGoogle Scholar
  6. Bhatia BB. On use of Rauwolfia serpentina in high blood pressure. J Indian Med. 1942;11:262–5.Google Scholar
  7. Chakravarty NK, Rai Chaudhuri MN, Chaudhuri RN. Rauwolfia serpentina in essential hypertension. Indian M Gaz. 1951;86:348–54.Google Scholar
  8. Dey A, De JN. Ethnobotanical aspects of Rauvolfia serpentina (L). Benth. ex Kurz. in India, Nepal and Bangladesh. J Med Plant Res. 2011;5:144–50.Google Scholar
  9. Dickinson A, MacKay D. Health habits and other characteristics of dietary supplement users: a review. Nutr J. 2014;13:14. doi: 10.1186/1475-2891-13-14.PubMedCentralCrossRefPubMedGoogle Scholar
  10. Dieterle F, Perentes E, Cordier A, Roth DR, Verdes P, Grenet O, et al. Urinary clusterin, cystatin C, β2-microglobulin and total protein as markers to detect drug-induced kidney injury. Nat Biotechnol. 2010;28:463–9. doi: 10.1038/nbt.1622.CrossRefPubMedGoogle Scholar
  11. Efrati S, Berman S, Tov YS, Averbukh Z, Weissgarten J. Hyperglycemia alters renal cell responsiveness to pressure in a model of malignant hypertension. J Hypertension. 2009;27:365–75. doi: 10.1097/HJH.0b013e32831b46ab.CrossRefGoogle Scholar
  12. Ezeigbo I, Ezeja M, Madubuike K, Ifenkwe D, Ukweni I, Udeh N, et al. Antidiarrhoeal activity of leaf methanolic extract of Rauwolfia serpentina. Asian Pac J Trop Biomed. 2012;2:430–2. doi: 10.1016/S2221-1691(12)60070-7.PubMedCentralCrossRefPubMedGoogle Scholar
  13. FDA.gov, C. for F.S. and A: Dietary supplements [WWW Document]. URL http://www.fda.gov/Food/DietarySupplements/default.htm (2014) Accessed 14 Nov 14).
  14. Gillespie C. After recalls, dietary supplements with banned drugs stay on market. Food Poison Bull;2014Google Scholar
  15. Gupta JC, Deb AK, Kahali BS. Preliminary observations on use of Rauwolfia serpentina Benth. in treatment of mental disorders. Indian M Gaz. 1943;78:547–9.Google Scholar
  16. Gupta MM, Srivastava A, Tripathi AK, Misra H, Verma RK. Use of HPTLC, HPLC, and densitometry for qualitative separation of indole alkaloids from Rauvolfia serpentina roots. JPCJ Planar Chromatogr Mod TLC. 2006;19:282–7.CrossRefGoogle Scholar
  17. Harel Z, Harel S, Wald R, Mamdani M, Bell CM. The frequency and characteristics of dietary supplement recalls in the United States. JAMA Intern Med. 2013;173:929–30. doi: 10.1001/jamainternmed.2013.379.CrossRefGoogle Scholar
  18. Hui KF, Lam BHW, Ho DN, Tsao SW, Chiang AKS. Bortezomib and SAHA synergistically induce ROS-driven caspase-dependent apoptosis of nasopharyngeal carcinoma and block replication of Epstein–Barr virus. Mol Cancer Ther. 2013;12:747–58. doi: 10.1158/1535-7163.MCT-12-0811.CrossRefPubMedGoogle Scholar
  19. Itoh A, Kumashiro T, Yamaguchi M, Nagakura N, Mizushina Y, Nishi T, et al. Indole alkaloids and other constituents of Rauwolfia serpentina. J Nat Prod. 2005;68:848–52. doi: 10.1021/np058007n.CrossRefPubMedGoogle Scholar
  20. Khandrika L, Koul S, Meacham RB, Koul HK. Kidney injury molecule-1 is up-regulated in renal epithelial cells in response to oxalate in vitro and in renal tissues in response to hyperoxaluria in vivo. PLoS ONE. 2012;7:e44174. doi: 10.1371/journal.pone.0044174.PubMedCentralCrossRefPubMedGoogle Scholar
  21. Klaassen C. Casarett & Doull’s toxicology: the basic science of poisons, Eighth edition. 8th ed. New York: McGraw-Hill Professional; 2013.Google Scholar
  22. Kumaria R, Rathib B, Ranic A, Bhatnagar S. Rauvolfia serpentina L. Benth. ex Kurz.: phytochemical. Pharmacol Ther Asp. 2013;56:348–55.Google Scholar
  23. Lindstrom A, Ooyen C, Lynch M, Blumenthal M, Kawa K. Sales of herbal dietary supplements increase by 7.9% in 2013, marking a decade of rising sales: turmeric supplements climb to top ranking in natural channel. HerbalGram. 2014;103:52–6.Google Scholar
  24. NIH.gov, D: Products by dietary ingredient of the Dietary Supplement Label Database (DSLD) [WWW Document]. URL http://dsld.nlm.nih.gov/dsld/rptIngredient.jsp?db=adsld&item=N%2CN-DIMETHYL-B-PHENYLETHYLAMINE+HCL (2015). Accessed 23 Mar 2015
  25. Ong ES. Extraction methods and chemical standardization of botanicals and herbal preparations. J Chromatogr B Analyt Technol Biomed Life Sci. 2004;812:23–33. doi: 10.1016/j.jchromb.2004.07.041.CrossRefPubMedGoogle Scholar
  26. Ott M, Gogvadze V, Orrenius S, Zhivotovsky B. Mitochondria, oxidative stress and cell death. Apoptosis. 2007;12:913–22. doi: 10.1007/s10495-007-0756-2.CrossRefPubMedGoogle Scholar
  27. Pathania S, Randhawa V, Bagler G. Prospecting for novel plant-derived molecules of Rauvolfia serpentina as inhibitors of aldose reductase, a potent drug target for diabetes and its complications. PLoS ONE. 2013;8:e61327. doi: 10.1371/journal.pone.0061327.PubMedCentralCrossRefPubMedGoogle Scholar
  28. Roy PK. Effect of Rauwolfia serpentina on manic patients. Indian J Neurol Psychiatry. 1950;2:59–62.Google Scholar
  29. Ryan MJ, Johnson G, Kirk J, Fuerstenberg SM, Zager RA, Torok-Storb B. HK-2: an immortalized proximal tubule epithelial cell line from normal adult human kidney. Kidney Int. 1994;45:48–57.CrossRefPubMedGoogle Scholar
  30. Sagi S, Avula B, Wang Y-H, Khan IA. Quantification and characterization of alkaloids from roots of Rauwolfia serpentina using ultra-high performance liquid chromatography-photo diode array-mass spectrometry. Anal Bioanal Chem. 2015. doi: 10.1007/s00216-015-9093-4.Google Scholar
  31. Singh S, Gupta Y, Kalra P, Karwasra R, Kumar R, Nayak D, et al. Evaluation of safety profile of homoeopathic mother tinctures. Indian J Res Homoeopathy. 2014;8:81. doi: 10.4103/0974-7168.135640.CrossRefGoogle Scholar
  32. Smith WM. Treatment of mild hypertension: results of a ten-year intervention trial. Circ Res. 1977;40:I98–105.CrossRefPubMedGoogle Scholar
  33. Sohn S-J, Kim SY, Kim HS, Chun Y-J, Han SY, Kim SH, et al. In vitro evaluation of biomarkers for cisplatin-induced nephrotoxicity using HK-2 human kidney epithelial cells. Toxicol Lett. 2013;217:235–42. doi: 10.1016/j.toxlet.2012.12.015.CrossRefPubMedGoogle Scholar
  34. Vaidya VS Bonventre JV Ferguson MA. Biomarkers of acute kidney injury, in: Comprehensive toxicology. Elsevier;2010. p. 1–15.Google Scholar
  35. Vakil RJ. A clinical trial of Rauwolfia serpentina in essential hypertension. Br Heart J. 1949;11:350–5. doi: 10.1136/hrt.11.4.350.PubMedCentralCrossRefPubMedGoogle Scholar
  36. Ware LB, Johnson ACM, Zager RA. Renal cortical albumin gene induction and urinary albumin excretion in response to acute kidney injury. Am J Physiol Ren Physiol. 2011;300:F628–38. doi: 10.1152/ajprenal.00654.2010.CrossRefGoogle Scholar
  37. Wilkins RW. Clinical usage of Rauwolfia alkaloids, including reserpine (serpasil). Ann N Y Acad Sci. 1954;59:36–44. doi: 10.1111/j.1749-6632.1954.tb45916.x.CrossRefPubMedGoogle Scholar
  38. Wilkins RW, Judson WE. The use of Rauwolfia serpentina in hypertensive patients. N Engl J Med. 1953;248:48–53. doi: 10.1056/NEJM195301082480202.CrossRefPubMedGoogle Scholar
  39. Wilkins RW, Judson WE, Stone RW, Hollander W, Huckabee WE, Friedman IH. Reserpine in the treatment of hypertension. N Engl J Med. 1954;250:477–8. doi: 10.1056/NEJM195403182501107.CrossRefPubMedGoogle Scholar
  40. Wu Y, Connors D, Barber L, Jayachandra S, Hanumegowda UM, Adams SP. Multiplexed assay panel of cytotoxicity in HK-2 cells for detection of renal proximal tubule injury potential of compounds. Toxicol Vitro Int J Publ Assoc BIBRA. 2009;23:1170–8. doi: 10.1016/j.tiv.2009.06.003.CrossRefGoogle Scholar
  41. Zhang L, Mu X, Fu J, Zhou Z. In vitro cytotoxicity assay with selected chemicals using human cells to predict target-organ toxicity of liver and kidney. Toxicol in Vitro. 2007;21:734–40. doi: 10.1016/j.tiv.2007.01.013.CrossRefPubMedGoogle Scholar

Copyright information

© US Government 2016

Authors and Affiliations

  • Miriam E. Mossoba
    • 1
    • 2
    Email author
  • Thomas J. Flynn
    • 1
  • Sanah Vohra
    • 1
  • Paddy L. Wiesenfeld
    • 1
  • Robert L. Sprando
    • 1
  1. 1.Center for Food Safety and Applied Nutrition (CFSAN), Office of Applied Research and Safety Assessment (OARSA), Division of Toxicology (DOT), Neurotoxicology and in vitro Toxicology Branch (NIVTB)U.S. Food and Drug Administration (US FDA)LaurelUSA
  2. 2.MOD-1 LaboratoriesUS FDALaurelUSA

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