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Angiotensin II-induced hypertension increases the mutant frequency in rat kidney

Abstract

Epidemiological studies revealed an increased risk for kidney cancer in hypertensive patients. In many of these patients, the blood pressure regulating renin–angiotensin–aldosterone system (RAAS) is activated. A stimulated RAAS leads to oxidative stress and increases markers of DNA damage, both in vitro and in animal models of hypertension. However, the mutagenic potential of RAAS activation has not been investigated yet. To quantify hypertension-induced mutations, BigBlue®+/− rats, which carry a transgenic lacI gene for mutation analysis, were treated for 20 weeks with a mean dose of 400 µg angiotensin II/kg × day. Angiotensin II-treated animals showed significantly increased blood pressure and impaired kidney function. Urinary excretion of oxidized nucleobases was raised. Additionally, in the renal cortex, oxidative stress, oxidatively generated DNA lesions and DNA strandbreaks were significantly increased. Further, a significant elevation of the mutant frequency in kidney DNA was detected. Sequencing revealed the presence of GC → T:A transversions in the mutated lacI genes of the angiotensin II-treated animals as a result of unrepaired oxidatively modified DNA bases, while no such transversions were found in the mutated lacI genes from control animals. The results demonstrate that the oxidative stress and DNA damage previously observed in kidney cells in vitro and in vivo after angiotensin II treatment indeed is associated with the accumulation of mutations in rat kidneys, providing further evidence for a cancer-initiating potential of elevated angiotensin II concentrations.

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Acknowledgements

The outstanding technical assistance of Kerstin De Mezzo is acknowledged. We thank Iris Schrey and Mandy Knitter for their excellent help during our operations, Stephanie Pohlmann for her help with the perfusion and Annegret Rosner and Wolfgang Manz for the considerate care of our rats.

Funding

This work was supported by the Deutsche Krebshilfe (#110667 to N. S. and #110668 to B. E.).

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Authors

Contributions

NS, and BE designed the study, CH and IS carried out experiments and analyzed the data, CH, NS and BE: drafted and revised the manuscript, all authors approved the final version of the manuscript.

Corresponding author

Correspondence to Nicole Schupp.

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The authors declare that they have no conflict of interest.

Ethical approval

All animal experiments were performed in accordance with the European Community guidelines for the use of experimental animals and with the German law for the protection of animals (Landesamt für Natur, Umwelt und Verbraucherschutz Nordrhein-Westfalen, permit number 84-02.04.2014.A386). The investigation conformed to the “Guide for the Care and Use of Laboratory Animals” published by the U.S. National Institutes of Health (NIH Publication No. 85-23, revised 1996).

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This article does not contain any studies with human participants performed by any of the authors.

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Hartmann, C., Schulz, I., Epe, B. et al. Angiotensin II-induced hypertension increases the mutant frequency in rat kidney. Arch Toxicol 93, 2045–2055 (2019). https://doi.org/10.1007/s00204-019-02477-8

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  • DOI: https://doi.org/10.1007/s00204-019-02477-8

Keywords

  • Angiotensin II
  • Hypertension
  • Mutation frequency
  • BigBlue®
  • 8-oxoG
  • Oxidative stress