Renal β-intercalated cells maintain body fluid and electrolyte balance
Victor Gueutin, … , Dominique Eladari, Régine Chambrey
Victor Gueutin, … , Dominique Eladari, Régine Chambrey
Published September 24, 2013
Citation Information: J Clin Invest. 2013;123(10):4219-4231. https://doi.org/10.1172/JCI63492.
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Research Article

Renal β-intercalated cells maintain body fluid and electrolyte balance

Abstract

Inactivation of the B1 proton pump subunit (ATP6V1B1) in intercalated cells (ICs) leads to type I distal renal tubular acidosis (dRTA), a disease associated with salt- and potassium-losing nephropathy. Here we show that mice deficient in ATP6V1B1 (Atp6v1b1–/– mice) displayed renal loss of NaCl, K+, and water, causing hypovolemia, hypokalemia, and polyuria. We demonstrated that NaCl loss originated from the cortical collecting duct, where activity of both the epithelial sodium channel (ENaC) and the pendrin/Na+-driven chloride/bicarbonate exchanger (pendrin/NDCBE) transport system was impaired. ENaC was appropriately increased in the medullary collecting duct, suggesting a localized inhibition in the cortex. We detected high urinary prostaglandin E2 (PGE2) and ATP levels in Atp6v1b1–/– mice. Inhibition of PGE2 synthesis in vivo restored ENaC protein levels specifically in the cortex. It also normalized protein levels of the large conductance calcium-activated potassium channel and the water channel aquaporin 2, and improved polyuria and hypokalemia in mutant mice. Furthermore, pharmacological inactivation of the proton pump in β-ICs induced release of PGE2 through activation of calcium-coupled purinergic receptors. In the present study, we identified ATP-triggered PGE2 paracrine signaling originating from β-ICs as a mechanism in the development of the hydroelectrolytic imbalance associated with dRTA. Our data indicate that in addition to principal cells, ICs are also critical in maintaining sodium balance and, hence, normal vascular volume and blood pressure.

Authors

Victor Gueutin, Marion Vallet, Maximilien Jayat, Janos Peti-Peterdi, Nicolas Cornière, Françoise Leviel, Fabien Sohet, Carsten A. Wagner, Dominique Eladari, Régine Chambrey

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Figure 7

Schematic description of the consequence of v-H+-ATPase dysfunction on Na+, K+, and water transport in the CNT/CCD and the MCD.

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Schematic description of the consequence of v-H+-ATPase dysfunction on N...
Atp6v1b1 disruption impairs both electroneutral Na+ absorption through β-ICs and ENaC-mediated Na+ absorption through the neighboring PCs. Local ATP/PGE2 signaling cascade is responsible for decreased ENaC protein and activity as well as AQP2 protein and contributes to Na+ and water losses, thereby promoting high tubular flow. ENaC inhibition in the CNT/CCD likely blocks K+ secretion through ROMK. In contrast, PCs in the MCD have a normal response to hyperaldosteronism (i.e. increased ENaC expression). Increased ENaC activity in the MCD is expected to favor K+ secretion through ROMK. High tubular flow activates BKCa potassium channels and K+ secretion, leading to renal K+ loss in Atp6v1b1–/– mice. Indeed, indomethacin, which reduced urinary flow and restored AQP2 protein levels in Atp6v1b1–/– mice, also normalized protein levels of BKCa and decreased urinary K+ excretion in Atp6v1b1–/– mice, leading to normal plasma potassium concentration.