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Mechanisms of Type I and Type II Pseudohypoaldosteronism

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Mechanisms of Type I and Type II Pseudohypoaldosteronism SCIENCE IN RENAL MEDICINE www.jasn.org Mechanisms of Type I and Type II Pseudohypoaldosteronism Seth B. Furgeson and Stuart Linas Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado, Aurora, Colorado ABSTRACT Pseudohypoaldosteronism (PHA) types I and II are curious genetic disorders that 100 cases with a similar syndrome (vari- share hyperkalemia as a predominant finding. Together they have become win- able levels of salt wasting, metabolic aci- dows to understanding new molecular physiology in the kidney. Autosomal reces- dosis, and hyperkalemia) have since been sive PHAI results from mutations in the epithelial sodium channel (ENaC), whereas described with both autosomal dominant autosomal dominant PHAI is characterized by mutations in the mineralocorticoid and recessive patterns of inheritance. In receptor. PHAII is the result of mutations in a family of serine-threonine kinases 1996, Chang et al.2 reported that autoso- called with-no-lysine kinases (WNK)1 and WNK4. WNK4 negatively regulates the mal recessive PHAI was caused by muta- NaCl cotransporter (NCC), and PHAII mutations in WNK4 abrogate this affect. tions of ENaC. Most cases of autosomal WNK4 also regulates the expression or function of renal outer medullary potassium dominant PHAI link to mutations in the (ROMK) channels, ENaCs, and Cl transporters. WNK1 also regulates NCC and mineralocorticoid receptor (MR).3 In gen- ROMK. Aldosterone inactivates WNK1 and WNK4 activity. Whether angiotensin II eral, patients with autosomal recessive can fine tune the actions of aldosterone is still unclear. PHAI, as opposed to patients with autoso- mal dominant PHAI, have a more severe J Am Soc Nephrol 21: 1842–1845, 2010. doi: 10.1681/ASN.2010050457 clinical phenotype and do not spontane- ously improve during early childhood. Furthermore, given the generalized expres- Nephrologists frequently encounter dis- though both hyperkalemia and volume sion of ENaC in epithelial tissues, autoso- orders involving aldosterone. Primary depletion stimulate aldosterone secre- mal recessive PHAI associates with sys- and secondary hyperaldosteronism, con- tion, the actions of aldosterone seem tai- temic manifestations, most notably, ditions in which aldosterone is elevated, are lored to the stimulus: potassium secre- recurrent pulmonary infections. typically characterized by variable levels of tion without volume overload in the first Although most patients with PHAI volume overload and hypokalemia. Con- situation and sodium reabsorption with- have an identifiable mutation, there are versely, patients with hypoaldosteronism out hypokalemia in the latter condition. still significant unknowns regarding the from primary adrenal insufficiency or hy- Here we briefly review the literature pathogenesis of PHAI. Whereas it is easy poreninemic hypoaldosteronism from di- regarding the pathogenesis of both to explain that loss of two copies of ENaC abetes frequently display hyperkalemia but pseudohypoaldosteronism type I (PHAI) will lead to sodium wasting and hyperka- may have no signs of volume depletion. and pseudohypoaldosteronism type II lemia, it has been less obvious how losing The major actions of aldosterone are (PHAII or Gordon’s syndrome). Although only one copy of the MR causes disease. well described in the cortical collecting both conditions have been recognized for Detailed studies of different MR muta- duct. Aldosterone increases the activity decades, emerging in vitro and in vivo data tions show that mutations can affect the of basolateral Na/K ATPase, luminal ex- provide new insights regarding the biologic pression of epithelial sodium channel effects of aldosterone and the variety of tar- Published online ahead of print. Publication date (ENaC), and the activity of luminal renal gets through which aldosterone may exert available at www.jasn.org. outer medullary potassium (ROMK) its actions. Correspondence: Dr. Stuart Linas, Division of Renal channels. There is, however, uncertainty Diseases and Hypertension, Department of Medi- regarding the molecular intermediates cine, University of Colorado–Denver, 12700 E. 19th PHAI and PHAII Avenue, C281, Aurora, CO 80045. Phone: 303-724- that transduce these actions. Further- 5063; Fax: 303-724-4831; E-mail: stuart.linas@ more, it is unclear why disorders involv- PHAI was first described in 1958 in an ucdenver.edu ing changes in levels of aldosterone have infant with recurrent episodes of volume Copyright © 2010 by the American Society of different phenotypes. For example, al- depletion and hyperkalemia.1 More than Nephrology 1842 ISSN : 1046-6673/2111-1842 J Am Soc Nephrol 21: 1842–1845, 2010 www.jasn.org SCIENCE IN RENAL MEDICINE N-terminal region, ligand-binding do- so named because of the lack of lysine in WNK4 increases chloride permeability main, or DNA-binding domain.3 Al- the ATP-binding cassette of the catalytic and PHAII-mutant WNK4 increases though functional studies using various region. Interestingly, patients with WNK1 chloride permeability even further.12 MR reporter assays showed that caus- mutations have intronic mutations that in- To date, two in vivo models have been ative mutations associate with less MR crease the abundance of WNK1, and pa- developed to study the role of WNK4 in activation in response to aldosterone, tients with WNK4 mutations have mis- mice. Lalioti et al.13 first described the gen- Geller et al.4 studied MR mutations in six sense mutations that localize to a short eration of a WNK4 transgenic mouse. families with autosomal dominant PHAI region in a highly conserved WNK residue. Three mouse populations, wild-type mice, and reported novel insights regarding mice expressing one extra copy of wild- some mutations. In one kindred, there type WNK4, and mice expressing two nor- was a C1984T mutation that converted mal copies of WNK4 and one WNK4 with G590 into a stop codon. In peripheral ROLE OF WNK1 AND WNK4 IN the Q562E mutation, were studied. Mice blood leukocytes, there was only mRNA ELECTROLYTE HANDLING overexpressing the PHAII mutation in for wild-type MR and no mRNA for mu- WNK4 display hypertension and hyper- tant MR. Therefore, rather than acting as Because patients with PHAII often have a kalemia. Additionally, PHAII-mutant a “dominant negative,” PHAI mutations dramatic response to thiazide diuretics, in- WNK4 transgenic mice exhibit metabolic in MR decrease amounts of cellular MR. vestigators first focused on the relationship acidosis and hypercalciuria, and the entire In this same report, these investigators between WNK1, WNK4, and the thiazide- phenotype is reversed when the mice are studied children and adults with PHAI sensitive NCC cotransporter. Indeed, two crossed with NCC knockout mice, impli- mutations and found adults were pheno- separate groups identified a relationship cating NCC hyperactivity as a major com- typically normal (other than elevated se- between WNK4 and NCC activity using ponent of the PHAII phenotype. rum aldosterone concentration) and Xenopus oocytes9,10; both groups showed Subsequently, Yang et al.14 generated many family members with PHA I muta- that wild-type WNK4 inhibited surface ex- a knock-in model of PHAII. To more tions never had any episodes of salt wast- pression of NCC and, consequently, NCC closely model human disease, these in- ing or hyperkalemia. Conversely, there activity. Mutant WNK4 isoforms have a vestigators generated mice with one nor- were four young children who were at variable effect on NCC activity, but one mal copy of WNK4 and one mutant risk for PHAI mutations who died at very WNK4 mutation seen in PHAII, WNK4 (D561A). Similar to human young ages, implying PHAI can some- Q562E, seems to diminish the ability of PHAII, the mice exhibited hypertension times present with a more severe pheno- WNK4 to regulate NCC. Given the and hyperkalemia that improves with type, leading to neonatal mortality. Such variable effects of different WNK4 iso- thiazide treatment. Urine potassium ex- data suggest two possibilities for under- forms, identifying precise molecular cretion also increases with Na2SO4. Ver- standing: one is that different MR muta- events that affect NCC activity, or ac- ifying in vitro data linking the Q562E tions have different effects on MR activa- company PHAII mutations in WNK4, mutation in WNK4 to increased NCC tion, and the other is that compensatory is still an active area of research. activity, WNK4 knock-in mice with a pathways modify disease phenotype. To study the mechanism of PHAII- PHAII mutation show increased phos- In 1964, the first case of PHAII was induced hyperkalemia, investigators have fo- phorylation and surface expression of reported.5 Rather than episodes of vol- cused on links between WNK4 and ROMK NCC. Similar to the early report, there is ume depletion, the teenage patient had potassium channels and chloride trans- no increase in overall levels of ROMK de- hypertension, severe hyperkalemia, and port. Using Xenopus oocytes or mam- spite hyperkalemia. mild metabolic acidosis. Six years later, malian cell lines, wild-type WNK4 de- Although there are not yet in vivo Gordon et al.6 reported another case of creases surface expression of ROMK, studies exploring the relationship be- PHAII. Similar to the first patient, this and PHAII-mutant WNK4 decreases it tween WNK1 and electrolyte transport- new patient also had low levels of plasma further.11 Because patients with PHAII ers, there are in vitro data showing such a renin, hyporesponsiveness to exogenous have increased urinary potassium
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