Aldosterone Induces DNA Damage and Activation of Nrf2 Mainly in Tubuli of Mouse Kidneys.

Ronja Balhorn,Nicole Schupp,Christina Hartmann

doi:10.3390/ijms21134679

Ronja Balhorn, Nicole Schupp + Show 1 more

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https://doi.org/10.3390/ijms21134679

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Abstract

Hypertensive patients have an increased risk of developing chronic kidney disease (CKD). Many of these patients have increased levels of the blood pressure regulating mineralocorticoid aldosterone. As a protection against aldosterone-induced damage, kidney cells can upregulate key regulators of the antioxidant defense, such as nuclear factor-erythroid-2-related factor 2 (Nrf2). In the present study aldosterone-induced kidney damage and Nrf2 activation in kidney cells of mice treated with three different concentrations of aldosterone for 4 weeks was localized. Increased albumin and neutrophil gelatinase-associated lipocalin (NGAL) in urine revealed an impaired kidney function of the aldosterone-infused mice. Localization of aldosterone-induced oxidative damage (in the form of DNA lesions) in specific kidney cells showed an increase in proximal tubuli and to an even greater extend in distal tubuli. Phosphorylated Nrf2 was increased in distal tubule cells after aldosterone-infusion. Nrf2 activation in proximal tubuli or in glomeruli after aldosterone-treatment could not be observed. Nrf2 target genes and proteins analyzed, paradoxically, showed a downregulation in the whole kidney. Aldosterone-treated mice exhibited an increased kidney injury and DNA damage in distal and proximal tubuli. Nrf2 seemed only to be specifically activated in distal tubule cells, where we also detected the highest amount of oxidative damage.

Highlights

Not many therapeutic options exist to decelerate progression of chronic kidney disease (CKD)
Oxidative stress is increased in CKD, documented by elevated levels of markers of lipid, protein, and DNA-oxidation in the serum of CKD patients compared to healthy controls [4,5,6] and endogenous antioxidant defense is reduced in CKD [7,8]
Kidney to body weight ratio was significantly higher in all dose groups, while heart to body weight ratio was significantly increased by the two higher aldosterone doses

Summary

Introduction

Not many therapeutic options exist to decelerate progression of CKD. Standard therapy at the moment is administration of inhibitors of the renin–angiotensin–aldosterone system (RAAS). Angiotensin converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARB) exert antihypertensive as well as anti-inflammatory and anti-fibrotic effects. The latter are explained by reduction of angiotensin II levels and subsequently aldosterone levels, which both are known to activate the pro-inflammatory transcription factor nuclear factor ‘kappa-light-chain-enhancer’ of activated B-cells (NF-κB), as well as the pro-fibrotic protein transforming growth factor-β (TGF-β). Aldosterone receptor antagonists reduce proteinuria and attenuate progressive renal disease, pointing to an important impact of aldosterone [1,2]. For example, the antioxidant N-acetylcysteine could ameliorate several endpoints of disease complication, like loss of glomerular filtration or cardiac events, no beneficial effects were observed on all-cause mortality [9]

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