Molecular pathogenesis of renal pseudohypoaldosteronism type 1

Pseudohypoaldosteronism is a rare heterogeneous syndrome of mineralocorticoid resistance resulting in insufficient potassium and hydrogen secretion. Pseudohypoaldosteronism type 1 is characterized by mineralocorticoid resistance leading to neonatal salt loss, dehydration and failure to thrive. At least two different forms of pseudohypoaldosteronism type 1 can be distinguished, showing either a systemic or renal form of mineralocorticoid resistance. This review offers an overview on transepithelial sodium reabsorption and pseudohypoaldosteronism in general, and focuses on the underlying molecular pathology of the renal-restricted pseudohypoaldosteronism type 1 form caused by heterozygous mutations in the mineralocorticoid receptor-coding gene NR3C2. The investigation of several NR3C2 mutants in vitro has resulted in important progress in the understanding of the physiology of the mineralocorticoid receptor. However, there are still some families or individuals suffering from renal pseudohypoaldosteronism type 1 in whom no genetic defect was found in the NR3C2 or other genes such as SCNN1A, SCNN1B, SCNN1G, NEDD4 or SGK1 that are involved in the epithelial salt transport machinery. Further research in these cases may enable the identification of other pathologies leading to renal pseudohypoaldosteronism type 1 and permit deeper insights into the epithelial sodium reabsorption process.