Metabolic acidosis causes a Fanconi-like syndrome with intracellular trafficking defects and proximal tubule dysfunction.

Patients suffering from distal renal tubular acidosis (dRTA) are sometimes diagnosed with proximal tubule dysfunction with leaks of phosphate, uric acid, amino acids, and low-molecular weight proteins, a condition also known as Fanconi-like syndrome. The underlying molecular basis is largely elusive. We previously reported on ATPase H+ transporting V0 subunit a4 (Atp6v0a4) knockout (KO) mice, which exhibit severe metabolic acidosis in combination with proximal tubule dysfunction as evidenced by phosphaturia and proteinuria. Here, we show that ras analog in brain 7 (Rab7), a key regulator of endolysosomal trafficking and lysosomal biogenesis, was diminished, and the number of abnormal lysosomal-associated membrane protein 1 (Lamp1)-positive vesicles labeled for increased sodium tolerance 1 (Ist1) was increased in proximal tubules of Atp6v0a4 KO mice. This was accompanied by the accumulation of autophagosomes, autolysosomes, and autophagic substrates. Correction of metabolic acidosis with bicarbonate therapy resolved proximal tubule dysfunction and trafficking defects in Atp6v0a4 KO mice. After 28 days of acid challenge, wild-type mice showed comparable trafficking defects to Rab7 down-regulation and an increase in Ist1-labeled Lamp1-positive vesicles and proximal tubule damage. Acidosis-induced decreases in RAB7-labeled particles and increased numbers of IST1-labeled LAMP1-positive particles also occurred in proximal tubule correlates of human kidney organoids derived from the widely used induced pluripotent stem cell line KOLF2.1J. Together, our data provide insight into why patients suffering from severe dRTA can develop a Fanconi-like syndrome, which may contribute to the progression of chronic kidney failure.