Suguru Nakamura

Deletion of the chloride transporter Slc26a7 causes distal renal tubular acidosis and impairs gastric acid secretion

SLC26A7 (human)/Slc26a7 (mouse) is a recently identified chloride-base exchanger and/or chloride transporter that is expressed on the basolateral membrane of acid-secreting cells in the renal outer medullary collecting duct (OMCD) and in gastric parietal cells. Here, we show that mice with genetic deletion of Slc26a7 expression develop distal renal tubular acidosis, as manifested by metabolic acidosis and alkaline urine pH. In the kidney, basolateral Cl−/HCO3− exchange activity in acid-secreting intercalated cells in the OMCD was significantly decreased in hypertonic medium (a normal milieu for the medulla) but was reduced only mildly in isotonic medium. Changing from a hypertonic to isotonic medium (relative hypotonicity) decreased the membrane abundance of Slc26a7 in kidney cells in vivo and in vitro. In the stomach, stimulated acid secretion was significantly impaired in isolated gastric mucosa and in the intact organ. We propose that SLC26A7 dysfunction should be investigated as a potential cause of unexplained distal renal tubular acidosis or decreased gastric acid secretion in humans.

HCO 3 − reabsorption in renal collecting duct of NHE-3-deficient mouse: a compensatory response

Mice with a targeted disruption of Na+/H+exchanger NHE-3 gene show significant reduction in[Formula: see text] reabsorption in proximal tubule, consistent with the absence of NHE-3. Serum[Formula: see text], however, is only mildly decreased (P. Schulties, L. L. Clarke, P. Meneton, M. L. Miller, M. Soleimani, L. R. Gawenis, T. M. Riddle, J. J. Duffy, T. Doetschman, T. Wang, G. Giebisch, P. S. Aronson, J. N. Lorenz, and G. E. Shull. Nature Genet. 19: 282-285, 1998), indicating possible adaptive upregulation of[Formula: see text]-absorbing transporters in collecting duct of NHE-3-deficient (NHE-3 -/-) mice. Cortical collecting duct (CCD) and outer medullary collecting duct (OMCD) were perfused, and total CO2 (net[Formula: see text] flux, J tCO2) was measured in the presence of 10 μM Schering 28080 (SCH, inhibitor of gastric H+-K+-ATPase) or 50 μM diethylestilbestrol (DES, inhibitor of H+-ATPase) in both mutant and wild-type (WT) animals. In CCD, J tCO2increased in NHE-3 mutant mice (3.42 ± 0.28 in WT to 5.71 ± 0.39 pmol ⋅ min-1 ⋅ mm tubule-1 in mutants, P < 0.001). The SCH-sensitive net[Formula: see text] flux remained unchanged, whereas the DES-sensitive [Formula: see text] flux increased in the CCD of NHE-3 mutant animals. In OMCD, J tCO2increased in NHE-3 mutant mice (8.8 ± 0.7 in WT to 14.2 ± 0.6 pmol ⋅ min-1 ⋅ mm tubule-1 in mutants, P < 0.001). Both the SCH-sensitive and the DES-sensitive [Formula: see text] fluxes increased in the OMCD of NHE-3 mutant animals. Northern hybridizations demonstrated enhanced expression of the basolateral Cl-/[Formula: see text]exchanger (AE-1) mRNA in the cortex. The gastric H+-K+-ATPase mRNA showed upregulation in the medulla but not the cortex of NHE-3 mutant mice. Our results indicate that[Formula: see text] reabsorption is enhanced in CCD and OMCD of NHE-3-deficient mice. In CCD, H+-ATPase, and in the OMCD, both H+-ATPase and gastric H+-K+-ATPase contribute to the enhanced compensatory[Formula: see text] reabsorption in NHE-3-deficient animals.

K+ depletion increases HCO3- reabsorption in OMCD by activation of colonic H(+)-K(+)-ATPase.

To probe the role of the isoforms of H(+)-K(+)-ATPase (HKA) in potassium depletion (KD), rats were placed on a KD diet for 2 wk. Colonic HKA (cHKA) mRNA levels increased approximately 30-fold in outer medulla, and net HCO3-flux (JtCO2) in outer medullary collecting duct (OMCD) increased (13.1 pmol.min-1.mm tubule length-1 in control to 17.7 pmol.min-1.mm tubule length-1 in KD; P < 0.01). In normal rats, 1 mM ouabain in perfusate had no effect on JtCO2, whereas 10 microM Sch-28080 decreased JtCO2 to 5.1 pmol.min-1.mm tubule length-1 (P < 0.001). In KD rats, ouabain 1 mM decreased JtCO2 to 6.3 pmol.min-1.mm tubule length-1 (P < 0.001). Although 10 microM Sch-28080 also decreased JtCO2 to 4.6 pmol.min-1.mm tubule length-1 (P < 0.001), the inhibitory effects of Sch-28080 and ouabain were not additive. Removal of K+ from perfusate blocked Sch-28080-sensitive JtCO2 in both normal and KD tubules. The data suggest that, in KD, cHKA is induced and mediates increased HCO3-reabsorption in OMCD, cHKA in vivo is sensitive to both Sch-28080 and ouabain, and cHKA activity is dominant.

787 Deletion of the Chloride/Base Exchanger Slc26a7 Impairs Gastric Acid Secretion and Causes Distal Renal Tubular Acidosis

G A A b st ra ct s located either in the proximal third of the corpus or in the fundus. Cardia tumors were classified according to the AEG-classification by Siewert and colleagues (AEG = adenocarcinoma of the esophagogastric junction; Siewert Br J Surg 1998). Included were tumors with their main tumor mass located directly at the cardia or subcardial with involvement of the cardia (AEG 2 and 3). Barrett carcinomas and supracardial cancers (AEG1) have been excluded. Patients were compared concerning the influence of H. pylori infection and the presence of histopathological changes. The chi-square test and consecutively Fishers exact test were used for statistical analysis. RESULTS: There was no difference in the prevalence of H. pylori in proximal versus distal GC. The histological differentiation between intestinal versus diffuse type cancers revealed significantly more intestinal type tumors at proximal location compared to distal GC (65 vs 46%; P = 0.022). Individual parameters of the proximal versus distal GC are reported in the table. Subanalysis of adenocarcinomas at the esophagogastric junction revealed no significant difference of H. pylori prevalence between cardial (AEG2) and subcardial (AEG3) tumors. CONCLUSION: There is no difference in the prevalence of H. pylori infection in proximal as compared to distal gastric cancer provided the allocation of the tumor is correctly assessed. To obtain correct prevalence data it is essential to exclude Barretts carcinomas (AEG1) from other adenocarcinomas at the esophagogastric junction. There was no distinct association of H. pylori with any of the histological types according to Lauren. Prevalence for H. pylori, CagA, IM and glandular atrophy by histolgical type and tumor location.