Angiotensin II-induced hypertension increases the mutant frequency in rat kidney
| Autor: | Ina Schulz, Christina Hartmann, Bernd Epe, Nicole Schupp |
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| Rok vydání: | 2019 |
| Předmět: |
Male
0301 basic medicine medicine.medical_specialty DNA damage Health Toxicology and Mutagenesis Renal cortex Mutant Blood Pressure 010501 environmental sciences Kidney Toxicology medicine.disease_cause 01 natural sciences Renin-Angiotensin System 03 medical and health sciences Internal medicine Renin–angiotensin system Lac Repressors medicine Animals Mutation frequency 0105 earth and related environmental sciences Chemistry Angiotensin II General Medicine Rats Oxidative Stress 030104 developmental biology medicine.anatomical_structure Endocrinology Hypertension Mutation Rats Transgenic Oxidative stress DNA Damage |
| Zdroj: | Archives of Toxicology. 93:2045-2055 |
| ISSN: | 1432-0738 0340-5761 |
| DOI: | 10.1007/s00204-019-02477-8 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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