US EPA

1782745 

Journal Article 

FUNCTION AND STRUCTURE OF H-K-ATPASE IN THE KIDNEY 

Wingo, CS; Smolka, AJ 

1995 

269 

1 

F1-F16 

7631822 

WOS:A1995RK17900001 

The present review summarizes recent functional and
structural evidence indicating that the kidney possesses at least one and probably more than one
isoform of a proton- and potassium-activated adenosinetriphosphatase (H-K-ATPase). Functional
studies have examined in detail the mechanism of luminal acidification and K/Rb absorption by the
outer medullary collecting duct (OMCD) from the inner stripe, a high-capacity distal site of
urinary acidification. These studies indicate that the mechanism of proton secretion in this
segment is similar to a model proposed for gastric acid secretion. Specifically, the profound
effect of H-K-ATPase inhibitors or luminal K removal on net bicarbonate (HCO3) absorption
indicates a major role for an H-K pump in luminal acidification by the OMCD. The importance of an
H-K-ATPase is further supported by the finding that nanomolar concentrations of bafilomycin A(1),
which specifically inhibit vacuolar-type H-ATPase, have significantly smaller effects on net HCO3
absorption than do H-K-ATPase inhibitors. Studies on the perfused inner medullary collecting duct
(IMCD) and cultured IMCD cells also suggest a significant role for H-K-ATPase in luminal
acidification by the IMCD. Evidence has accrued from studies in the cortical CD and OMCD that the
mechanism of H-K-ATPase-mediated luminal proton secretion differs under K-replete and K-
restricted conditions. In K repletion, luminal K ions transported by the pump recycle back into
the lumen by a Ba-sensitive mechanism. However, in K restriction, the mechanism of the H-K-ATPase
involves luminal proton secretion and K absorption that is insensitive to luminal Ba and, by
inference, apical K recycling. Moreover, in K restriction, K/Rb absorption is inhibited by
basolateral Ba, indicating that the pump operates to reabsorb K/Rb across the epithelium. The
structural evidence reviewed here indicates the presence of mRNA within the mammalian kidney that
is either identical or highly homologous to mRNAs for gastric and putative colonic H-K-ATPase
alpha-subunits and gastric H-K-ATPase beta-subunit. Localization of these transcripts by in situ
hybridization demonstrates gastric alpha- and beta-subunit mRNAs in intercalated cells of both
the cortical and medullary CD, principal cells of the CD, and IMCD cells. Additional studies in
transgenic mice indicate that regulatory sequences upstream to the H-K-ATPase beta-subunit gene
direct transcription in both gastric parietal cells and the renal CD. Elucidation of the
physiological function of H-K-ATPase and the first and second messenger systems responsible for
H-K-ATPase activation or inhibition will remain an area of particular interest for the
foreseeable future. Answers to such questions will likely provide considerable insight into whole
kidney physiology and will require, of necessity, a full spectrum of physiological, biochemical,
anatomical, and molecular biological techniques. 

INNER MEDULLARY COLLECTING DUCT; CORTICAL COLLECTING DUCT; PROTON POTASSIUM ACTIVATED ADENOSINE-TRIPHOSPHATASE; RUBIDIUM; BARIUM; BAFILOMYCIN; TRANSGENIC; ALPHA-SUBUNIT; BETA-SUBUNIT; TRANSPORT; SCH-28080