Lithium-Induced Disruption of Intracellular Ca2+ Balance in the Collecting Duct Intercalated Cells Contributes to Metabolic Acidosis in Mice

INTRODUCTION. Lithium (Li+) is an effective mood stabilizer that continues to be widely used in modern psychiatric practice. One of the most common adverse effects of Li+ therapy is nephrogenic diabetes insipidus manifesting in reduced urinary concentrating ability due to impaired vasopressin (AVP) signaling in the collecting duct principal cells. While distal tubular acidosis has also been reported in patients receiving Li+, molecular determinants underlying the pathophysiological effects of Li+ on the collecting duct intercalated cells and renal acid-base transport remain to be fully elucidated. Activation of Gq-coupled vasopressin 1a receptors (V1aR) in A-intercalated cells reportedly induces intracellular Ca2+ ([Ca2+]i) mobilization and stimulates luminal H+ secretion, resulting in urine acidification. OBJECTIVE. The objective of this study was to test if Li+ impaired V1aR-induced [Ca2+]i response in the intercalated cells of murine collecting ducts. HYPOTHESIS. We hypothesized that Li+ markedly impaired V1aR-dependent [Ca2+]i signaling in A-intercalated cells causing the reduction of luminal proton secretion in the collecting duct. METHODS. We combined immunofluorescent imaging in freshly isolated collecting duct segments with metabolic cage studies in C57BL/6NJ (Jackson Labotatory) mice receiving a regular Teklad 2918 chow (control) or a Teklad 2918-based diet containing 0.3% lithium carbonate (Li+-treated) to evaluate how Li+ affects V1aR-mediated [Ca2+]i signal, H+ transport by intercalated cells, as well as urinary pH and ammonia excretion. RESULTS. We found that AVP elicited a transient [Ca2+]i response in the aquaporin-2 (AQP2) negative cells from collecting duct segments isolated from control mice. The response was mediated by Ca2+ release from the endoplasmic reticulum (ER), as it was inhibited by pretreatment of collecting duct segments with thapsigargin, a SERCA pump inhibitor. The amplitude of the AVP-induced calcium transient was 4 times lower in the AQP2-negative cells isolated from Li+-treated mice. Li+ intake remarkably facilitated store-operated calcium entry (SOCE) in the collecting duct cells, indicating chronic ER depletion and stress. At the systemic level Li+-treated mice exhibited urine alkalinization (by 0.8 pH units) and a 6-fold elevation in urinary ammonium excretion, when compared to controls. CONCLUSIONS. Intracellular Ca2+ signaling in the intercalated cells is an essential determinant of acid-base handling in the collecting duct. Our findings reveal that Li+ markedly alters [Ca2+]i signaling in the intercalated cells, causing urine alkalinization and elevated ammonium excretion, likely, to compensate for ensuing metabolic acidosis. NIDDK R01DK125464. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.