30 YEARS OF THE MINERALOCORTICOID RECEPTOR: Mineralocorticoid receptor and NaCl transport mechanisms in the renal distal nephron

Abstract

A key role of aldosterone and mineralocorticoid receptor is to regulate fluid volume and K + homeostasis in the body by acting on the renal distal nephron. Global responses of the kidney to elevated aldosterone levels are determined by the coordinate action of different constituent tubule cells, including principal cells, intercalated cells and distal convoluted tubule cells. Recent studies on genetic mutations causing aldosterone overproduction have identified the molecules involved in aldosterone biosynthesis in the adrenal gland, and there is also increasing evidence for mechanisms and signaling pathways regulating the balance between renal NaCl reabsorption and K + secretion, the two major effects of aldosterone. In particular, recent studies have demonstrated that mineralocorticoid receptor in intercalated cells is selectively regulated by phosphorylation, which prevents ligand binding and activation. Moreover, the ubiquitin ligase complex composed of Kelch-like 3 and Cullin 3 acts downstream of angiotensin II and plasma K + alterations, regulating Na-Cl cotransporter independently of aldosterone in distal convoluted tubule cells. These and other effects are integrated to produce appropriate kidney responses in a high-aldosterone state, and are implicated in fluid and electrolyte disorders in humans. This review summarizes the current knowledge on mechanisms modulating mineralocorticoid receptor and its downstream effectors in the distal nephron.

Differential impacts of mineralocorticoid receptor antagonist potassium canrenoate on liver and renal changes in high fat diet-mediated early hepatocarcinogenesis model rats

“…The preventive effects of PC on the HFD-induced basophilic tubules may be related to MR/ NOX signaling pathway (Whaley-Connell et al, 2010), since the basophilic tubules expressed MR and p22phox as demonstrated by immunohistochemistry. The immuno-positive reaction of MR in the cytoplasms and nuclei was confirmed in the distal tubules and collecting tubules in kidney sections, as reported previously (Lombès et al, 1990), and supporting the role of MR in sodium absorption and potassium retention by regulating Na-Cl cotransporter in these tubules (Shibata, 2017). The biological significance of nuclear localization of MR in basophilic tubules remains uncertain.…”

The mineralocorticoid receptor is essential for stress axis regulation in zebrafish larvae

“…In mammals, in addition to aldosterone, the glucocorticoids are also a major ligand of MR; however, almost all the mineralocorticoid functions are mediated by aldosterone-MR signalling 5 . The high affinity of cortisol for MR means that aldosterone-mediated effects occur in tissues where 11β-hydroxysteroid dehydrogenase 2 (11β-HSD2), a key enzyme that breaks down cortisol, is prevalent.…”

Antagonistic effects of finerenone and spironolactone on the aldosterone‐regulated transcriptome of human kidney cells

“…The encoded proteins are highly important in sodium reabsorption (epithelial Na + channel, ENaC) including the maintenance of sodium and potassium channels to the membrane (GILZ), and the maintenance of the mineralocorticoid signaling pathway (FKBP5 and USP2). 48 Aldosterone is known to promote inflammation in the kidney during CKD, through the promotion of macrophages infiltration and maturation. 49 At a systemic level, it also represses inflammation (interleukins) and favors fibrosis protein markers (CTGF, TGF-β2) directly in epithelial cells.…”