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

The present review summarizes recent functional and structural evidenc e indicating that the kidney possesses at least one and probably more than one isoform of a proton- and potassium-activated adenosinetriphos phatase (H-K-ATPase). Functional studies have examined in detail the m echanism of luminal acidification and K/Rb absorption by the outer med ullary collecting duct (OMCD) from the inner stripe, a high-capacity d istal site of urinary acidification. These studies indicate that the m echanism of proton secretion in this segment is similar to a model pro posed 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 acidifica tion by the OMCD. The importance of an H-K-ATPase is further supported by the finding that nanomolar concentrations of bafilomycin A(1), whi ch specifically inhibit vacuolar-type H-ATPase, have significantly sma ller effects on net HCO3 absorption than do H-K-ATPase inhibitors. Stu dies on the perfused inner medullary collecting duct (IMCD) and cultur ed IMCD cells also suggest a significant role for H-K-ATPase in lumina l 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 i nto 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, apic al K recycling. Moreover, in K restriction, K/Rb absorption is inhibit ed by basolateral Ba, indicating that the pump operates to reabsorb K/ Rb across the epithelium. The structural evidence reviewed here indica tes the presence of mRNA within the mammalian kidney that is either id entical or highly homologous to mRNAs for gastric and putative colonic H-K-ATPase alpha-subunits and gastric H-K-ATPase beta-subunit. Locali zation of these transcripts by in situ hybridization demonstrates gast ric alpha- and beta-subunit mRNAs in intercalated cells of both the co rtical and medullary CD, principal cells of the CD, and IMCD cells. Ad ditional 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 physi ological function of H-K-ATPase and the first and second messenger sys tems responsible for H-K-ATPase activation or inhibition will remain a n area of particular interest for the foreseeable future. Answers to s uch questions will likely provide considerable insight into whole kidn ey physiology and will require, of necessity, a full spectrum of physi ological, biochemical, anatomical, and molecular biological techniques .