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

Abstract

<jats:p>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.</jats:p>

Nrf2 Activation Does Not Protect from Aldosterone-Induced Kidney Damage in Mice

“…Again, as previously reported, Aldo treatment in mice did not induce Nrf2 target genes as we previously observed in rats [ 11 , 15 ], consistent with reports of downregulated Nrf2 targets from the human situation in CKD and other animal CKD models [ 5 , 16 ]. Unexpectedly, based on our previously conducted rat study with Sulf as the Nrf2 activator [ 11 ], Sulf had no effect at all on Nrf2 target genes, either alone or in combination with Aldo.…”

“…That the decreased amount of Keap1 basally has no direct effect on Nrf2 expression has also been observed previously by another group, but does not indicate anything about the posttranslational regulation of Nrf2 [ 37 ]. Looking closer at the localization of Nrf2, in these groups of animals, as in the preparatory experiment [ 15 ], a significantly increased Nrf2 amount was shown in all Aldo-treated groups only in the cortex, not in the medulla of the kidney. Too large interindividual differences among the animals prevented an evaluation of the presence of Nrf2 in the nucleus.…”

“…To examine the effects of Nrf2 activation on moderate renal injury, we chose an Aldo concentration that did not persistently increase blood pressure significantly above normal but produced measurable histological and physiological changes in the kidney [ 15 ]. These changes to the kidney were different in the treatment groups and showed higher damage to the glomeruli and moderate protection of the tubules in the Aldo-treated Nrf2ꜛ animals, whereas the Nrf2 activator Sulf appeared to provide mild protection of the glomeruli in the WT mice, but none to their tubuli.…”

“…New, specific protein–protein inhibitors of the Keap1–Nrf2 interaction are being explored at the moment but have not yet reached the clinic [ 13 ]. We have recently shown that in mice with moderate kidney injury caused by increased Aldo concentrations the expression of Nrf2 target genes in kidney cells was significantly reduced despite an increased abundance of Nrf2 and its putatively activated phosphorylated form in the kidney [ 15 ]. Similar findings have been observed in patients with advanced CKD [ 16 ] and also in animal models of CKD [ 5 , 17 ].…”

Comprehensive Bioinformatics Analysis Identifies POLR2I as a Key Gene in the Pathogenesis of Hypertensive Nephropathy

“…The GSVA analysis of POLR2I showed that many gene sets associated with oxidative stress were downregulated in the POLR2I high-expression groups (Figure 10A), suggesting the potential functions of POLR2I in renal oxidative stress damage associated with HN. Consistent with our enrichment analysis results (Figure 6A), there is evidence that oxidative stress is an important driving factor of the pathogenesis and progression of HN (Wilcox, 2005;Balhorn et al, 2020). Oxidative stress can induce DNA damage, which can be fatal to cells if not repaired (You et al, 2020).…”