Abstract
Chronic glucocorticoid infusion impairs NCC activity and induces a non-dipping profile in mice, suggesting that glucocorticoids are essential for daily blood pressure variations. In this paper, we studied mice lacking the renal tubular glucocorticoid receptor (GR) in adulthood (GR knockouts, Nr3c1Pax8/LC1). Upon standard salt diet, Nr3c1Pax8/LC1 mice grow normally, but show reduced NCC activity despite normal plasma aldosterone levels. Following diet switch to low sodium, Nr3c1Pax8/LC1 mice exhibit a transient but significant reduction in the activity of NCC and expression of NHE3 and NKCC2 accompanied by significant increased Spak activity. This is followed by transiently increased urinary sodium excretion and higher plasma aldosterone concentrations. Plasma corticosterone levels and 11βHSD2 mRNA expression and activity in the whole kidney remain unchanged. High salt diet does not affect whole body Na+ and/or K+ balance and NCC activity is not reduced, but leads to a significant increase in diastolic blood pressure dipping in Nr3c1Pax8/LC1 mice. When high sodium treatment is followed by 48 h of darkness, NCC abundance is reduced in knockout mice although activity is not different. Our data show that upon Na+ restriction renal tubular GR-deficiency transiently affects Na+ handling and transport pathways. Overall, upon standard, low Na+ and high Na+ diet exposure Na+ and K+ balance is maintained as evidenced by normal plasma and urinary Na+ and K+ and aldosterone concentrations.
Highlights
The glucocorticoid receptor (GR, Nr3c1) belongs to the same nuclear steroid receptor family as the mineralocorticoid receptor (MR, Nr3c2) and acts as ligand-dependent transcription factor
Whole kidney lysates from Nr3c1Pax8/LC1 mice exhibited an about 80% reduced Nr3c1 mRNA transcript and protein expression (Figure 1A, left panel and Figure 1B), and tubular microdissection revealed a near-complete absence of Nr3c1 protein in all tubular segments with the exception of the DCT/CNT which showed a significantly reduced Nr3c1 expression (Figure 1C and Supplementary Figures S1A,B)
In contrast to GR, MR (Nr3c2) mRNA expression was not affected in the whole kidney of Nr3c1Pax8/LC1 mutant mice (Figure 1A, right panel)
Summary
The glucocorticoid receptor (GR, Nr3c1) belongs to the same nuclear steroid receptor family as the mineralocorticoid receptor (MR, Nr3c2) and acts as ligand-dependent transcription factor. It binds corticosteroid hormones like cortisol (human) and corticosterone (rodents) (Lu et al, 2006). Ackermann et al (2010) proposed that ligand-induced nuclear translocation of both steroid receptors may be part of a segment- and cell type-specific regulation in the kidney, as a differential nuclear translocation was observed upon corticosteroid treatment along the rat nephron. Under stress conditions, when free cortisol (or corticosterone) reaches high levels, amiloridesensitive sodium transport is stimulated despite intact 11β-HSD2 expression or activity, possibly as a result of 11β-HSD2 saturation (Odermatt et al, 2001). Glucocorticoid treatment transiently changes the renal clock gene transcription and influences peripheral clocks, the underlying mechanism is not yet completely defined (Balsalobre et al, 2000; Sujino et al, 2012)
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