Mineralocorticoid Receptor Antagonists Cause Natriuresis in the Absence of Aldosterone.

MR (mineralocorticoid receptor) antagonists are recommended for patients with resistant hypertension even when circulating aldosterone levels are not high. Although aldosterone activates MR to increase epithelial sodium channel (ENaC) activity, glucocorticoids also activate MR but are metabolized by 11βHSD2 (11β-hydroxysteroid dehydrogenase type 2). 11βHSD2 is expressed at increasing levels from distal convoluted tubule (DCT) through collecting duct. Here, we hypothesized that MR maintains ENaC activity in the DCT2 and early connecting tubule in the absence of aldosterone. We studied AS (aldosterone synthase)-deficient (AS <sup>-/-</sup> ) mice, which were backcrossed onto the same C57BL6/J strain as kidney-specific MR knockout (KS-MR <sup>-/-</sup> ) mice. KS-MR <sup>-/-</sup> mice were used to compare MR expression and ENaC localization and cleavage with AS <sup>-/-</sup> mice. MR was highly expressed along DCT2 through the cortical collecting duct (CCD), whereas no 11βHSD2 expression was observed along DCT2. MR signal and apical ENaC localization were clearly reduced along both DCT2 and CCD in KS-MR <sup>-/-</sup> mice but were fully preserved along DCT2 and were partially reduced along CCD in AS <sup>-/-</sup> mice. Apical ENaC localization and ENaC currents were fully preserved along DCT2 in AS <sup>-/-</sup> mice and were not increased along CCD after low salt. AS <sup>-/-</sup> mice exhibited transient Na <sup>+</sup> wasting under low-salt diet, but administration of the MR antagonist eplerenone to AS <sup>-/-</sup> mice led to hyperkalemia and decreased body weight with higher Na <sup>+</sup> excretion, mimicking the phenotype of MR <sup>-/-</sup> mice. Our results provide evidence that MR is activated in the absence of aldosterone along DCT2 and partially CCD, suggesting glucocorticoid binding to MR preserves sodium homeostasis along DCT2 in AS <sup>-/-</sup> mice

Molecular analysis of B-cell differentiation in selective or partial IgA deficiency

Selective IgA deficiency is the most common form of primary immunodeficiency, the molecular basis of which is unknown. To investigate the cause of selective IgA deficiency, we examined what stage of B-cell differentiation was blocked. DNA and RNA were extracted from three Japanese patients with selective IgA deficiency and three with a partial IgA deficiency. In selective IgA deficiency patients, Iα germline transcript expression levels decreased and α circle transcripts were not detected. Stimulation with PMA and TGF-β1 up-regulated Iα germline and α circle transcripts. In some patients, IgA secretion was induced by stimulation with anti-CD40, IL-4 and IL-10. In partial IgA deficiency patients, Iα germline, α circle transcripts and Cα mature transcripts were detected in the absence of stimulation. Our findings suggest that the decreased expression level of Iα germline transcripts before a class switch might be critical for the pathogenesis of some patients with selective IgA deficiency. However, in patients with a partial IgA deficiency, B-cell differentiation might be disturbed after a class switch