Changes in V-ATPase subunits of human urinary exosomes reflect the renal response to acute acid/alkali loading and the defects in distal renal tubular acidosis

Pathare, Ganesh Tukaram; Dhayat, Nasser; Mohebbi, Nilufar; Wagner, Carsten A.; Bobulescu, Alexandru; Moe, Orson W.; Fuster, Daniel Guido (2018). Changes in V-ATPase subunits of human urinary exosomes reflect the renal response to acute acid/alkali loading and the defects in distal renal tubular acidosis. Kidney international, 93(4), pp. 871-880. Elsevier 10.1016/j.kint.2017.10.018

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In the kidney, final urinary acidification is achieved by V-ATPases expressed in type A intercalated cells. The B1 subunit of the V-ATPase is required for maximal urinary acidification, while the role of the homologous B2 subunit is less clear. We examined the effect of acute acid/alkali loading in humans on B1 and B2 subunit abundance in urinary exosomes in normal subjects and of acid loading in patients with distal renal tubular acidosis (dRTA). Specificities of B1 and B2 subunit antibodies were verified by yeast heterologously expressing human B1 and B2 subunits, and murine WT and B1-deleted kidney lysates. Acute NH4Cl loading elicited systemic acidemia, drop in urinary pH, and increase in urinary NH4 excretion. Nadir urinary pH was achieved at 4-5 h, and exosomal B1 abundance was significantly increased at 2 h until 6 h after
NH4Cl loading. After acute equimolar NaHCO3 loading, blood and urinary pH rose rapidly, with concomitant reduction of exosomal B1 abundance within 2 h and B1 abundance remained lower throughout the test. In contrast, no changes in exosomal B2 abundance were observed following acid or alkali loading. In patients with inherited or acquired dRTA, urinary B1 subunit was extremely low or undetectable and did not respond to acid loading in urine, whereas no change in B2 subunit was observed. In summary, both B1 and B2 subunits of the V-ATPase are detected in human urinary exosomes, and acid and alkali loading or dRTA cause changes in the B1 but not B2 subunit abundance in urinary exosomes.

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