Kidney Vacuolar H
-ATPase:
Physiology and Regulation
Patricia Valles, Michael S. Lapointe, Jan Wysocki, and Daniel Batlle
The vacuolar H
-ATPase is a multisubunit protein consisting of a peripheral catalytic
domain (V
1
) that binds and hydrolyzes adenosine triphosphate (ATP) and provides energy
to pump H
through the transmembrane domain (V
0
) against a large gradient. This proton-
translocating vacuolar H
-ATPase is present in both intracellular compartments and the
plasma membrane of eukaryotic cells. Mutations in genes encoding kidney intercalated
cell–specific V
0
a4 and V
1
B1 subunits of the vacuolar H
-ATPase cause the syndrome of
distal tubular renal acidosis. This review focuses on the function, regulation, and the role
of vacuolar H
-ATPases in renal physiology. The localization of vacuolar H
-ATPases in the
kidney, and their role in intracellular pH (pHi) regulation, transepithelial proton transport,
and acid-base homeostasis are discussed.
Semin Nephrol 26:361-374 © 2006 Elsevier Inc. All rights reserved.
KEYWORDS renal vacuolar H
-ATPase, ATP6V1B1 subunit, ATP6V0A4 subunit, distal tubular
renal acidosis (dRTA)
T
he vacuolar proton-translocating adenosine triphos-
phatases (ATPases) are a family of multisubunit ATP-
driven proton pumps present in both intracellular compart-
ments and the plasma membrane of eukaryotic cells.
1-3
They
couple the energy released on ATP hydrolysis to the active
transport of protons from the cytoplasm to either the lumen
of various intracellular compartments or to the extracellular
environment. Acidification of intracellular compartments is
important for such processes as receptor-mediated endocy-
tosis, intracellular trafficking of lysosomal enzymes, degrada-
tion of macromolecules, uptake of neurotransmitters, and the
entry of various envelope viruses and toxins.
4-6
Vacuolar H
+
-
ATPases located in the cell membranes of many different cell
types mediate proton extrusion from the cell.
7
This acidifica-
tion of the extracellular environment often is linked to spe-
cialized cell function. Examples include osteoclasts where
protons generated by the vacuolar H
+
-ATPases are used to
dissolve bone matrix, and macrophages where an acidic ex-
tracellular pH is involved in killing and digesting neighbor-
ing cells or pathogens.
8
In addition, vacuolar H
+
-ATPases in
other cells regulate the extracellular pH of closed extracel-
lular compartments such as in the inner-ear endolymph
fluid
9-11
or acidification of seminal fluid in the epididymis.
12
Perhaps the most significant function of vacuolar H
+
-
ATPases is in epithelia, where their role in acid/base transport
and transepithelial transport is crucial for many physiologic
processes.
This review focuses on the function and regulation of vac-
uolar H
+
-ATPases in renal physiology and pathophysiology.
Structure and
Molecular Organization
of Vacuolar H
-ATPases
Vacuolar H
+
-ATPases belong to the large superfamily
of ATPases, which is subdivided into 3 major subclasses:
(1) P-type ATPases such as Na
+
/K
+
-ATPases, Ca
2+
-
ATPases, and H
+
/K
+
-ATPases, (2) mitochondrial F
1
F
0
-
ATPases, and (3) V-type (vacuolar) H
+
-ATPases (http://
www.gene.ucl.ac.uk/nomenclature/).
13
Mitochondrial F
1
F
0
-ATPases and vacuolar H
+
-ATPases
share many structural features in their subunit composition
such as amino acid sequences and subunit arrangements.
14
Functionally, however, they are distinguished by the fact that
F
1
F
0
-ATPases use a proton gradient for ATP synthesis
whereas vacuolar H
+
-ATPases use ATP hydrolysis to gener-
ate a proton gradient.
15
From the Area de Fisiopatología, Departamento de Patología, Facultad de
Ciencias Médicas, Universidad Nacional de Cuyo, Mendoza, Argentina;
Department of Biology, Indiana University Northwest, Gary, IN; and the
Division of Nephrology and Hypertension, Department of Medicine,
Northwestern University, The Feinberg School of Medicine, Chicago, IL.
Address reprint requests to Daniel Batlle, MD, Division of Nephrology and
Hypertension, The Feinberg School of Medicine, Northwestern Univer-
sity, Searle 10-475, 320 E. Superior, Chicago, IL 60611. E-mail:
d-batlle@northwestern.edu
361 0270-9295/06/$-see front matter © 2006 Elsevier Inc. All rights reserved.
doi:10.1016/j.semnephrol.2006.07.004