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

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Background: The blood pressure-regulating hormone aldosterone is genotoxic in vitro in kidney cells in nanomolar concentrations, and provoked DNA damage in kidneys of aldosterone-treated animals. Epidemiological studies have found an increased kidney cancer risk in hypertensive patients. In up to 13-20% of these patients plasma aldosterone levels are elevated. During the last project period, we found DNA damage caused by aldosterone not only in its primary target cells, cells of the distal tubulus, but also in cells of the proximal tubulus, which give rise to the majority of kidney tumors. An induction of anti-apoptotic and a decrease of pro-apoptotic proteins was detected, supporting our hypothesis of a tumorigenic potential of aldosterone. Aldosterone also activates the main regulator of the antioxidative cellular defense, the transcription factor Nrf2. An even more pronounced activation of Nrf2 by the isothiocyanate sulforaphane protected kidneys of aldosterone-treated animals from damage and lowered their blood pressure.Project content: Using mice with a specific deletion of the inhibitor of Nrf2, Keap1, in kidney cells to be determined in an upstream pilot experiment, the question will be addressed if a locally defined activation of Nrf2 is sufficient to protect kidney cells from aldosterone-induced damage. This mouse will also show if this activation contributes to the blood pressure lowering, or if a systemic activation of Nrf2 is needed for this effect. With a phospho-protein array, mouse kidney tissue will be screened for signal transduction pathways modulated by aldosterone. The activation/inhibition and renal localisation of substantially regulated candidate proteins will be detected on kidney tissue of mice and rats. Further, it will be tested, if the activation of the already known pro-survival signals, and of signals identified by the array, takes place in cells which simultaneously show DNA damage. Emphasis will be placed on the study of the mentioned effects in low dose ranges, doses which can be expected in the plasma of hypertensive individuals.Aims: The anticipated results of the present project will help to elucidate the role of the antioxidative defense in the kidney. Currently, there is a great interest in activators of Nrf2 as possible drugs to treat acute and chronic kidney failure. Here, we can contribute to the understanding of Nrf2 effects in the kidney with mechanistical data. Findings gained from analyzing the signaling pathways might define the next steps in clarifying the question if endogenous substances can act as carcinogenesis initiating factors, playing a role in spontaneous developing malignancies.