Identification of target cells for aldosterone-induced genotoxicity and characterisation of aldosterone effects with regard to the triggering of pro-survival pathways in kidney cells
Final Report Abstract
The endogenous hormones angiotensin II and aldosterone, which are elevated in hypertension, induce oxidative stress and DNA damage in the kidney. Since hypertensive individuals also show an increased risk of kidney cancer, the effects mediated by the hormones could be involved in the development of tumors. In the present project, we investigated in which renal cells the hormone aldosterone acts primarily adversely, whether it has an effect on renal cell division and death, and whether induction of antioxidant defenses can protect against its unfavorable effects. The cells most affected by adverse effects of aldosterone were localized in the renal cortex and could be identified as cells of the distal tubule in the mice we studied, although cells of the proximal tubule and glomerulus also exhibited oxidative damage at higher concentrations. In cell culture experiments, aldosterone has been shown to activate signaling pathways that lead to the prevention of cell death on the one hand and the promotion of cell division on the other - key events in cancer initiation and development. Increased cell division and decreased cell death in some parts of the kidney were also found in vivo. Key factors activated by aldosterone were the cancer-promoting transcription factors STAT3 and CREB. Analysis of changes in the phosphorylation status of over 30 proteins confirmed effects of aldosterone on signaling pathways we had previously studied and revealed an additional signaling pathway that plays a role in the antioxidant defense of kidney cells, the GSK3β/Fyn axis. We found this to be deregulated in the kidneys of aldosterone-treated animals. It could be the cause of our unexpected finding that activation of the regulator of antioxidant defense, the transcription factor Nrf2, failed to protect against oxidative damage by aldosterone in the animals, in contrast to the in vitro experiments performed. Thus, incorrect phosphorylation in this pathway may lead to downregulation of antioxidant factor expression despite the presence of an activated Nrf2. In summary, this project thus identified the target cells of the adverse aldosterone effects and revealed the unfavorable aldosterone effects on cell division and death and on antioxidant defense in chronic kidney disease. This may help in the future development of drugs to treat this disease.
Publications
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Aldosterone Activates Transcription Factor Nrf2 in Kidney Cells Both In Vitro and In Vivo. Antioxidants & Redox Signaling, 21(15), 2126-2142.
Queisser, Nina; Oteiza, Patricia I.; Link, Samuel; Hey, Valentin; Stopper, Helga & Schupp, Nicole
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Aldosterone induces fibrosis, oxidative stress and DNA damage in livers of male rats independent of blood pressure changes. Toxicology and Applied Pharmacology, 280(3), 399-407.
Queisser, Nina; Happ, Kathrin; Link, Samuel; Jahn, Daniel; Zimnol, Anna; Geier, Andreas & Schupp, Nicole
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Aldosterone activates the oncogenic signals ERK1/2 and STAT3 via redox‐regulated mechanisms. Molecular Carcinogenesis, 56(8), 1868-1883.
Queisser, Nina; Schupp, Nicole; Schwarz, Eva; Hartmann, Christina; Mackenzie, Gerardo G. & Oteiza, Patricia I.
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Curcumin Ameliorates Kidney Function and Oxidative Stress in Experimental Chronic Kidney Disease. Basic & Clinical Pharmacology & Toxicology, 122(1), 65-73.
Ali, Badreldin H.; Al‐Salam, Suhail; Al Suleimani, Yousuf; Al Kalbani, Jamila; Al Bahlani, Shadia; Ashique, Mohammed; Manoj, Priyadarsini; Al Dhahli, Buthaina; Al Abri, Nadia; Naser, Heba T.; Yasin, Javed; Nemmar, Abderrahim; Al Za'abi, Mohammed; Hartmann, Christina & Schupp, Nicole
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Aldosterone Induces DNA Damage and Activation of Nrf2 Mainly in Tubuli of Mouse Kidneys. International Journal of Molecular Sciences, 21(13), 4679.
Balhorn, Ronja; Hartmann, Christina & Schupp, Nicole
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Nrf2 Activation Does Not Protect from Aldosterone-Induced Kidney Damage in Mice. Antioxidants, 12(3), 777.
Brinks, Ronja; Wruck, Christoph Jan; Schmitz, Jutta & Schupp, Nicole
