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

Int J Mol Sci. 2020 Jun 30;21(13):4679. doi: 10.3390/ijms21134679.

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.

Keywords: Nrf2; aldosterone; chronic kidney disease; distal tubuli; kidney damage.

MeSH terms

  • Aldosterone / administration & dosage
  • Aldosterone / blood*
  • Animals
  • Blood Pressure
  • DNA Damage
  • Kidney / metabolism*
  • Kidney / pathology
  • Male
  • Mice, Inbred C57BL
  • NF-E2-Related Factor 2 / metabolism*
  • Renal Insufficiency, Chronic / blood*
  • Renal Insufficiency, Chronic / pathology

Substances

  • NF-E2-Related Factor 2
  • Nfe2l2 protein, mouse
  • Aldosterone