Increased Na reabsorption via the Na–Cl cotransporter in autosomal recessive pseudohypoaldosteronism

Abstract

The autosomal recessive form of pseudohypoaldosteronism type 1 (AR-PHA1) is caused by loss-of-function mutations in the epithelial sodium channel subunit genes and is characterized by a multisystemic and lifelong severe salt-wasting tendency. However, we observed a male AR-PHA1 patient who exhibited less frequent salt wasting with advancing age, despite the cessation of daily salt supplementation. To elucidate the mechanism for the above phenomenon. We evaluated the sodium-reabsorption ability of his distal nephrons (from the distal convoluted tubules to the collecting ducts) and compared it to that of a patient with the dominant form of PHA1 (AD-PHA1) carrying a heterozygous NR3C2 (mineralocorticoid receptor) gene mutation. In addition, immunoblotting of the thiazide-sensitive Na(+)-Cl(-) cotransporter (NCC) protein was conducted using urine samples from the AR- and AD-PHA1 patients. The levels of sodium reabsorption that occurred via the distal nephrons were almost identical in the two PHA1 patients, despite their different molecular pathogeneses. Immunoblotting showed an increased urinary NCC protein level in the AR-PHA1 patient. Taken together, increased sodium reabsorption via the upregulation of the expression of NCC might have been responsible, at least in part, for the clinical improvement seen in an AR-PHA1 patient.