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 2

Differential effects of Atp6v1b1 disruption on the cortical and MCD.

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Differential effects of Atp6v1b1 disruption on the cortical and MCD. (...
(A) Effects of Atp6v1b1 disruption on NaCl transport in the CCD. JNa and JCl were measured in CCDs isolated from Atp6v1b1+/+ mice and Atp6v1b1–/– mice fed a salt-depleted diet for 2 weeks. n = 5–7 tubules from different mice in each group. *P < 0.05. ***P < 0.001, 2-tailed unpaired Student’s t test. (B) Effects of Atp6v1b1 disruption on ENaC and pendrin expression in the CCD. α-ENaC, γ-ENaC, and pendrin protein abundance were assessed with Western blot of protein extracted from the renal cortex of Atp6v1b1–/– and Atp6v1b1+/+ mice. (C) Effects of Atp6v1b1 disruption on ENaC expression in the MCD. α-ENaC and γ-ENaC protein abundance was assessed with Western blot of protein extracted from the renal medulla of Atp6v1b1–/– and Atp6v1b1+/+ mice. (B and C) Lanes were loaded with a protein sample from different mice, with 15 μg (B) and 5 μg (C) proteins per lane; equal loading confirmed by parallel Coomassie-stained gels. The α-ENaC antibody recognized 2 bands at 90 and 100 kDa. Bands at 90 kDa (arrows) were not detected in kidneys from α-ENaC knockout mice, and were quantified. The γ-ENaC antibody recognized a doublet band at 85–80 kDa and a large band centered around 70 kDa (brackets). Bar graphs summarize densitometric analyses of doublet 85-kDa and broad 70-kDa bands. *P < 0.05, **P < 0.01, ***P < 0.001 vs. Atp6v1b1+/+, unpaired Student’s t test. (D) Effect of amiloride on urinary Na+ excretion in Atp6v1b1+/+ and Atp6v1b1–/– mice. Urines were collected before and 6 hours after amiloride injection (1.45 mg/kg BW) into Atp6v1b1+/+ and Atp6v1b1–/– mice. *P < 0.05 vs. Atp6v1b1+/+ after amiloride injection; **P < 0.01, ***P < 0.001 vs. basal state; 1-way ANOVA.