Mineralocorticoid Resistance

David S. Geller


Clin Endocrinol. 2005;62(5):513-520. 

In This Article

Pseudohypoaldosteronism Type 2

Pseudohypoaldosteronism type 2 (PHA2) is a rare Mendelian disorder characterized by the autosomal dominant transmission of hypertension, hyperkalaemia and metabolic acidosis with normal renal function, with the salient finding that thiazide diuretics rapidly ameliorate all clinical findings. In contrast to PHA1, serum aldosterone levels are either low or normal, and thus the term 'pseudohypoaldosteronism' is somewhat of a misnomer. Nevertheless, the failure of the kidney to appropriately secrete potassium in this condition suggests a degree of aldosterone resistance, and recent data on cellular mechanisms underlying PHA2 are instructive for the understanding of clinical syndromes of aldosterone resistance.

Some years ago, two loci for PHA2 were identified on chromosomes 1 and 17 by linkage analysis but the precise molecular defect remained unknown. Recently, however, a novel form of the disorder linking to chromosome 12p13 was identified,[45,46] and Wilson et al . demonstrated that affected members in these kindreds carry large deletions in the first intron of a serine—threonine kinase called WNK1.[46] The mutation results in an upregulation of WNK1 mRNA expression, although the mechanism by which this results in hypertension and hyperkalaemia is not entirely clear.[46] Wilson et al . further identified a family of novel WNK1 paralogues and demonstrated that mutations in one of these, WNK4, cause PHA2 in kindreds linking to chromosome 16. The disease-causing mutations in WNK4 are missense mutations that alter a highly conserved 10-amino-acid sequence of the encoded protein.

The WNK kinases are so named because they lack a conserved lysine residue seen in the catalytic domain of the kinase domain of all other serine kinases (WNK = with no lysine [K]). WNK1 is expressed widely throughout the body, whereas WNK4 is limited to the distal nephron. Recently, there has been remarkable progress in understanding the mechanism by which mutations in WNK1 and WNK4 cause hyperkalaemia and hypertension. In vitro , WNK4 acts as a negative regulator of the thiazide-sensitive cotransporter NCCT, and furthermore, mutant WNK4 molecules identified in patients with PHA2 lose their ability to inhibit NCCT.[47,48] Further evidence suggests that WNK1 acts as a negative regulator of WNK4.[48] These activities of WNK1 and WNK4 suggest a straightforward mechanism for the hypertension observed in PHA2 patients, through the loss of regulation of distal nephron sodium reabsorption. However, the mechanism by which these mutations result in hyperkalaemia would not be explained by these findings. Kahle et al. ,[49] however, recently demonstrated that WNK4 also inhibits the renal K+ channel ROMK used in distal nephron potassium secretion, and that the same WNK4 mutations that relieve NCCT inhibition increase inhibition of ROMK. These data support the hypothesis that WNK4 functions as a molecular switch that regulates the balance between sodium reabsorption and potassium secretion necessary for integrated homeostasis and is probably a key regulator of the aldosterone effector pathway.[49] Moreover, they provide a compelling explanation for the underlying pathophysiology of PHA2, and provide a novel mechanism for mineralocorticoid resistance in the distal nephron. As WNK4-mediated regulation of sodium transport in the kidney relies on a mechanism distinct from the mechanism regulating potassium balance, it seems plausible that natriuretic agents lacking the often dose-limiting side-effects of hypokalaemia (thiazide diuretics) or hyperkalaemia (antimineralocorticoids) could one day be developed.