Dysregulation of ATP6V1B1 in renal intercalated cells in the pathophysiology of type 4 renal tubular acidosis.

Type 4 renal tubular acidosis (RTA) is a common disorder characterized by hyperkalemic non-anion gap metabolic acidosis. Although type 4 RTA is generally attributed to impaired renal ammoniagenesis induced by hyperkalemia, whether defects in distal nephron acidification contribute to its pathophysiology remains unclear. Here, we investigated alterations in distal nephron acidification machinery in Kelch-like 3 knock-in (KLHL3-KI) mice, a genetically engineered model of pseudohypoaldosteronism type II. KLHL3-KI mice exhibited hyperkalemia, hyperchloremia, and reduced serum bicarbonate levels, consistent with type 4 RTA. Phosphoenolpyruvate carboxykinase (PEPCK), a key enzyme involved in proximal tubular ammoniagenesis, was significantly reduced in KLHL3-KI mice as compared with wild-type mice. In addition, ATP6V1B1, a subunit of the vacuolar H+-ATPase selectively expressed in intercalated cells, was significantly decreased in membrane fraction. Renal medullary expression of Rh C glycoprotein (RHCG), a major ammonia transporter in the distal nephron, was also reduced. To determine whether these changes were secondary to hyperkalemia, KLHL3-KI mice were fed a low-K+ diet. Correction of hyperkalemia with a low-K+ diet significantly increased RHCG abundance, whereas ATP6V1B1 levels remained unchanged. By immunostaining, we found that WNK1 bodies were detected in a subset of ATP6V1B1-positive cells. In sum, these findings demonstrate that distal nephron acidification pathways are dysregulated in KLHL3-KI mice. Whereas RHCG downregulation appears to be potassium-dependent, ATP6V1B1 reduction persists despite correction of hyperkalemia, suggesting the involvement of potassium-independent mechanisms. Our findings raise the possibility that dysregulated KLHL3 signaling contributes to impaired distal nephron acidification in type 4 RTA, which merits further investigation.