Aldosterone induces oxidative stress, oxidative DNA damage and NF-κB-activation in kidney tubule cells
Department of Toxicology, University of Würzburg, Würzburg, Germany. Molecular Carcinogenesis
(Impact Factor: 4.81).
02/2011; 50(2):123-35. DOI: 10.1002/mc.20710
An increase of the mineralocorticoid aldosterone is induced by a stimulated renin-angiotensin system in a subgroup of hypertensive patients. Epidemiological studies find higher cancer mortality in hypertensive patients and an increased risk to develop kidney cancer. This work investigated the involvement of oxidants in the genotoxicity of aldosterone and on a potential activation of transcription factor nuclear factor-κB (NF-κB) in kidney tubule cells. Aldosterone, at concentrations as low as 1 nM caused a significant increase of DNA damage, as assessed by comet assay and micronucleus frequency test. Aldosterone also led to a dose-dependent activation of NF-κB. Time courses of DNA damage and NF-κB-activation showed that these effects already occurred after 5 and 3 min of aldosterone exposure, respectively, suggesting non-genomic events of the hormone. Antioxidants prevented aldosterone-induced DNA damage and NF-κB-activation, indicating the involvement of oxidants. In fact, aldosterone caused an increase in intracellular oxidant levels, and in particular of superoxide anions. As a consequence, increased levels of the oxidized DNA modification 7,8-dihydro-8-oxo-guanine were observed in aldosterone-treated kidney cells. Aldosterone-induced DNA damage and NF-κB-activation was dependent on the involvement of the mineralocorticoid receptor. The induction of oxidant-mediated genotoxic effects, and of a long-term activation of the potentially oncogenic cell signal NF-κB by aldosterone could contribute to the increased kidney cancer incidence in hypertensive patients.
Available from: Gil Facina
- "In 2012, the estimated number of new breast cancer cases is above two-hundred and twenty-nine thousand . Among the various mediators that act in the carcinogenic process, the components of the renin-angiotensin system (RAS) have assumed an important role    . Angiotensin II (Ang II), better known peptide obtained from the cascade of events of RAS, has vasoconstrictive, angiogenic, hyperplastic, proliferative and metastatic properties  . "
Available from: Quaisar Ali
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ABSTRACT: The renin-angiotensin system (RAS) is a hormonal cascade that acts together to regulate blood pressure. Angiotensin II (Ang II) is the major octapeptide of RAS and mediates its cellular and physiological actions by acting on AT 1 and AT 2 receptor. Most of the cellular and physiological actions of Ang II such as cellular growth and proliferation, vasoconstriction, antinatriuresis and increase in blood pressure are mediated via AT 1 receptor. The functions associated with the AT 2 receptors are less studied, in part, due to its lower expression in adult tissues. However, AT 2 receptor has been suggested as functional antagonist of AT 1 re-ceptors and thereby opposes the actions of Ang II mediated via AT 1 receptor. Thus, the activation of AT 2 receptors has been shown to cause vasodilatation, natriuresis and decrease in blood pressure. After the discovery of the AT 2 receptor in various parts of the kidney, including in proximal tubules, there has been an interest in establishing a link between the renal AT 2 receptor, renal Na-excretion and blood pressure regulation. Earlier, we have reported that activation of renal AT 2 receptors increases urinary Na excretion in obese Zucker rats, in part via inhibiting Na + /K + -ATPase (NKA) activity and stimulating nitric oxide/cGMP pathway in the proximal tubules. An impaired pressure natriuresis and increased AT 1 recep-tor function is believed to be the cause of hypertension in obese Zucker rats and other animal models of obesity. In this review, we are focussing on the role of renin angiotensin system especially AT 2 receptors in obesity associated hypertension.
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ABSTRACT: Klotho, a transmembrane protein, protease, and hormone mainly expressed in renal tissue counteracts aging. Overexpression of Klotho substantially prolongs the life span. Klotho deficiency leads to excessive formation of 1,25(OH)(2)D(3), growth deficit, accelerated aging, and early death. Aging is frequently paralleled by dehydration, which is considered to accelerate the development of age-related disorders. The present study explored the possibility that dehydration influences Klotho expression. Klotho transcript levels were determined by RT-PCR, and Klotho protein abundance was detected by Western blotting in renal tissue from hydrated and 36-h-dehydrated mice as well as in human embryonic kidney (HEK293) cells. Dehydration was followed by a significant decline of renal Klotho transcript levels and protein abundance, accompanied by an increase in plasma osmolarity as well as plasma ADH, aldosterone, and 1,25(OH)(2)D(3) levels. Antidiuretic hormone (ADH; 50 nM) and aldosterone (1 μM) significantly decreased Klotho transcription and protein expression in HEK293 cells. In conclusion, the present observations disclose a powerful effect of dehydration on Klotho expression, an effect at least partially mediated by enhanced release of ADH and aldosterone.
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