234 1 S SHIBATA Transport mechanisms in the 234:1 T35–T47 Thematic Review renal distal nephron 30 YEARS OF THE MINERALOCORTICOID RECEPTOR Mineralocorticoid receptor and NaCl transport mechanisms in the renal distal nephron Correspondence Shigeru Shibata1,2 should be addressed 1Division of Nephrology, Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan to S Shibata 2Division of Clinical Epigenetics, Research Center for Advanced Science and Technology, University of Tokyo, Email Tokyo, Japan shigeru.shibata@med. teikyo-u.ac.jp Abstract A key role of aldosterone and mineralocorticoid receptor is to regulate fluid volume Key Words and K+ homeostasis in the body by acting on the renal distal nephron. Global responses f angiotensin of the kidney to elevated aldosterone levels are determined by the coordinate action f plasma K of different constituent tubule cells, including principal cells, intercalated cells and f KLHL3 Endocrinology distal convoluted tubule cells. Recent studies on genetic mutations causing aldosterone f ubiquitin proteasome of overproduction have identified the molecules involved in aldosterone biosynthesis in system the adrenal gland, and there is also increasing evidence for mechanisms and signaling f phosphorylation pathways regulating the balance between renal NaCl reabsorption and K+ secretion, Journal 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 Journal of Endocrinology distal nephron. (2017) 234, T35–T47 Introduction The main function of the kidney is to maintain constant cells of the adrenal cortex and it regulates Na+, K+ and Cl− fluid volume and composition by altering the functioning balance in the body mainly by acting on the distal part of the of various cells lining the nephron. Changes in electrolyte renal nephron (which normally includes distal convoluted balance are transmitted to individual cells through multiple tubules (DCTs), connecting tubules and collecting duct). signaling pathways, inducing appropriate responses to Although NaCl reabsorbed in the distal segment represents physiological perturbations and altered intake. The steroid only a fraction of that handled by the nephron, fine tuning hormone aldosterone is produced in zona glomerulosa occurs in this segment, which determines total body salt http://joe.endocrinology-journals.org © 2017 Society for Endocrinology This paper is part of a thematic review section on 30 Years of the Mineralocorticoid DOI: 10.1530/JOE-16-0669 Published by Bioscientifica Ltd. Receptor. The guest editors for this section were John Funder and Printed in Great Britain Maria Christina Zennaro. Downloaded from Bioscientifica.com at 10/02/2021 08:39:18PM via free access 10.1530/JOE-16-0669 Thematic Review S SHIBATA Transport mechanisms in the 234:1 T36 renal distal nephron and water content. Cells of the distal nephron also play responses upon physiological perturbations and under important roles in controlling extracellular K+ levels, pathological conditions is also discussed. and dysregulation of transporters and channels in these segments is a major cause of altered blood pressure and Role of principal cells in NaCl and plasma K+ levels (Lifton et al. 2001, Boyden et al. 2012). K+ regulation Aldosterone is produced in two distinct physiological states, hypovolemia (intravascular volume depletion) Principal cells express epithelial Na+ channel (ENaC), a and hyperkalemia. In the former, activation of the renin– heterotrimeric protein composed of α, β and γ subunits angiotensin system induces angiotensin II (AngII) type (Pearce et al. 2015). While most Na+ transport occurring 1 receptor signaling in glomerulosa cells, stimulating in the renal tubules is coupled to the transport of other aldosterone biosynthesis via Ca2+ signaling (Spat & anions or cations (e.g., Na+–H+ exchanger 3 or Na+–glucose Hunyady 2004, Boulkroun et al. 2015). On the other cotransporters in the proximal tubules, Na+–K+–2Cl- hand, hyperkalemia stimulates aldosterone production cotransporter 2 in the thick ascending limb and Na–Cl by directly depolarizing the cells and activating cotransporter (NCC) in the DCT), only Na+ ions are voltage-gated Ca2+ channels (Spat & Hunyady 2004, transported through ENaC. This electrogenic Na+ Boulkroun et al. 2015). Aldosterone, in turn, increases reabsorption generates a lumen-negative potential, and mineralocorticoid receptor (MR) transcriptional activity establishes an electrochemical gradient that drives Cl− in the distal nephron and regulates the activity of and K+ transport. Loss-of-function mutations in this electrolyte transport mediators, which maximizes either channel not only affect Na+ reabsorption but also perturb NaCl reabsorption or K+ secretion depending on the Cl− and K+ transport (Lifton et al. 2001). Conversely, gain- physiological context. Recent genetic studies of familial of-function mutations in this channel cause high blood electrolyte imbalances as well as biochemical analyses of pressure and hypokalemia (Table 1) (Shimkets et al. 1994, renal electrolyte flux regulators and upstream signaling Staub et al. 1996, Kamynina & Staub 2002). As discussed pathways have provided insights into the molecular later, the most important regulator of ENaC is aldosterone. Endocrinology mechanisms that modulate the action of aldosterone in Apical K+ secretion in principal cells is a critical of the distal nephron. In this review, the current knowledge determinant of the amount of K+ excreted in urine and it on mechanisms that regulate electrolyte flux mediators is regulated by renal outer medullary K+ (ROMK) channel. in cells lining the distal nephron is summarized (i.e., + Journal Like other inwardly rectifying K channels, ROMK forms principal cells, intercalated cells, and DCT cells (Fig. 1)). a tetramer and is highly selective for K+ over Na+ and Accumulating evidence indicates that both MR-dependent other ions. The ROMK gene contains several exons that and -independent factors are involved. In addition, how produce alternatively spliced transcripts, and principal these mechanisms are integrated to produce appropriate cells of the cortical collecting duct express ROMK1 and Figure 1 Cells comprising the renal distal nephron. Distal convoluted tubule (DCT) cells express thiazide- sensitive Na–Cl cotransporter (NCC) at the apical membrane. Principal cells of the collecting duct express epithelial Na+ Channel (ENaC) and renal outer medullary K+ channel (ROMK) at the apical membrane. Intercalated cells are divided into three types; α-intercalated cells express H+-ATPase, whereas β-intercalated cells express − − Cl /HCO3 exchanger pendrin at the apical membrane. Non-α, non-β intercalated cells are characterized by the expression of both pendrin and H+-ATPase at the apical membrane. http://joe.endocrinology-journals.org © 2017 Society for Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/JOE-16-0669 Printed in Great Britain Downloaded from Bioscientifica.com at 10/02/2021 08:39:18PM via free access Thematic Review S SHIBATA Transport mechanisms in the 234:1 T37 renal distal nephron Table 1 Human conditions related to dysregulation of MR or downstream effectors in the distal nephron.* Disease or disorder Clinical characteristics Genetic cause or suggested mechanism Pseudohypoaldosteronism type 1 (PHAI) Neonatal salt wasting, hyperkalemia, Loss-of-function mutation in MR or ENaC metabolic acidosis Hypertension exacerbated by pregnancy Early onset hypertension, markedly MR mutation leading to activation by accelerated in pregnancy steroids lacking 21-hydorxyl (e.g., progesterone) Apparent mineralocorticoid excess (AME) Early onset hypertension, MR activation by cortisol due to hypokalemia, metabolic alkalosis mutation in 11βHSD2 Liddle syndrome Early onset hypertension and Mutation in ENaCβ or γ resulting in hypokalemic alkalosis reduced clearance by Nedd4-2 Gitelman syndrome Hypokalemia, metabolic alkalosis, Loss-of-function mutation in NCC mild hypotension Pendred syndrome Hearing loss and thyroid Loss-of-function mutation in pendrin abnormality; potential for hypokalemia, metabolic alkalosis and fluid loss Pseudohypoaldosteronism type 2 (PHAII or FHHt) Hypertension, hyperkalemia and NCC overactivity due to mutation in metabolic acidosis KLHL3/CUL3 or WNK Licorice-induced hypertension Hypertension, hypokalemia, Inhibition of 11βHSD2 by glycerrhetinic metabolic alkalosis acid CNI-induced hypertension Hypertension associated with the use NCC activation via WNK-SPAK pathway of CNIs such as tacrolimus and cyclosporine *Disorders resulting from the increased circulating mineralocorticoids are not included in the table. 11βHSD2, 11β-hydroxysteroid dehydrogenase 2; CNI, calcineurin inhibitor; CUL3, cullin-3; ENaC, epithelial Na channel; FHHt, familial hyperkalemic hypertension; KLHL3, Kelch-like 3; MR,