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 E 2 (PGE 2 ) and ATP levels in Atp6v1b1 -/-mice. Inhibition of PGE 2 synthesis in vivo restored ENaC protein levels specifically in the cortex. It also normalized protein levels of the large conductance calciumactivated 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 PGE 2 through activation of calcium-coupled purinergic receptors. In the present study, we identified ATP-triggered PGE 2 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.

Collecting Duct Intercalated Cell Function and Regulation

“…The maintenance of the apical and basolateral domains of the kidney tubular epithelium depends on the presence of functional tight junctions, the differential permeabilities of the two membranes, and the generation of gradients between the lumen and the interstitium. Recent findings have uncovered the paracrine signals that integrate the function of intercalated and principal cells in the collecting duct (35).…”

“…| Model of major transport processes and regulatory mechanisms in type B intercalated cells. This cartoon is modified from the model proposed by Chambrey and colleagues (35). These cells participate in electroneutral NaCl absorption, which is energized by H 1 -ATPase.…”

New insights into sodium transport regulation in the distal nephron: Role of G-protein coupled receptors

“…These results suggest that P2Y2 are important activators of the cellular production of paracrine and autocrine messengers known to down-regulate the main sodium transporters in the nephron [213] . Gueutin et al [117] recently found that mouse…”

“…However, this effect was not observed in the rat CCD [112] . Investigation of the regulatory system involving prostaglandin and their receptors has led to the identification of a cross-talk between the intercalated and PC of the CCD (see below) [117] . FP receptors are present in rabbit DCT cells and CCD PC where their activation was shown to inhibit sodium and water reabsorption [118] .…”

“…Interestingly, activation of the purinergic receptor induces the release of PGE2, which is known to inhibit sodium and water absorption in the distal nephron through the activation of EP1, EP3 and EP4 as described above. The effects of ATP through P2Y2 activation or those of PGE2 through PE receptors on the Na + /Cl -electroneutral transport system in IC remain unknown [117] .…”