How Does Aldosterone Work in the β-Intercalated Cell?

Aldosterone is a steroid hormone produced by the cells of the zona glomerulosa in the adrenal glands serving both K⁺ and volume homeostasis. One key physiologic function is to guard our potassium homeostasis, and aldosterone is liberated in response to increased plasma levels of potassium. Aldosterone effectively increases the renal K⁺ excretion by upregulating molecular players that support K⁺ secretion primarily in the collecting duct (CD). One of the major players in this regard is the epithelial sodium channel (ENaC), where increased expression of functional channels in the apical membrane will provide the depolarization needed to support sustained K⁺ secretion via renal outer medullary K⁺. A K⁺ load, in parallel to liberating aldosterone, also reduces the effective Na⁺ reabsorption via NaCl cotransporter in the distal convoluted tubule, and consequently, Na⁺ reabsorption is effectively shifted to the more distally located CD allowing K⁺ secretion. Under states of volume depletion, the renin-angiotensin-aldosterone system is activated,and here, aldosterone plays the other important role, namely it stimulates ENaC function to safeguard against any loss of Na⁺ into the urine that might occur. The central role of aldosterone in the regulation of fluid and electrolyte balance is clearly illustrated in states of excessive hormone concentrations (e.g., in aldosterone-producing adenomas). In aldosterone-producing adenomas, the increase of kaliuresis becomes visible as marked K⁺ wasting and hypokalemia, whereas the increased ENaC function results in volume expansion and thus, hypertension. Aldosterone elicits most of its effects via the cytoplasmic mineralocorticoid receptor (MR), which during binding of the steroid molecule, detaches from the chaperone heat shock protein 90, moves into the nucleus, and functions as a transcription factor to alter cellular expression of key proteins. In the connecting tubule and CD, the MR is found in principal cells, and here, the actions of aldosterone have been extensively studied over the last decades. The absorption of Na⁺ in the CD is paralleled by the absorption of Cl⁻ via the SLC26A4 transporter pendrin in the CD β-intercalated cells (β-ICs).¹ It was previously documented that Na⁺ restriction upregulates pendrin, possibly mediated by aldosterone.^2,3 It was also shown that Cl⁻ absorption in CD depended substantially on the presence of pendrin.¹ The molecular mechanism that upregulates pendrin by elevated aldosterone is not understood. Intercalated cells (ICs) do express MRs, and thus, aldosterone could potentially mediate its effect directly via the IC-MR.⁴ This would imply that aldosterone via the MR regulates ENaC-dependent Na⁺ transport in the principal cells in concert with pendrin-dependent Cl⁻ transport in the neighboring β-IC. In this issue of JASN, Pham et al.⁵ have addressed whether this is the case. The authors have successfully created an IC-specific knockout mouse of the MR. They clearly document that the absence of MR in IC significantly reduces pendrin protein expression and function. This correlates with lower CD Cl⁻ absorption and therefore, clearly defines a role of the IC-MR as a modulator of CD Cl⁻ absorption. However, the question remains whether the MR in IC in vivo is primarily activated by aldosterone or glucocorticoids. The specificity of aldosterone signaling is jeopardized by glucocorticoids that are found at about 100-fold higher plasma concentrations. Mineralocorticoids and glucocorticoids bind with approximately equal affinity at the MR.⁶ Therefore, a highly efficient glucocorticoid scavenging system (the 11 β Hydroxysteroid Dehydrogenase type 2 [11-β-HSD2] enzyme) is used in many MR-expressing systems.⁶ In the ICs, this glucocorticoid-eliminating system has low functionality if any, and hence, the MR should, in principle, be active at all times^4,7 as a result of the ubiquitous presences of high glucocorticoid levels. Thus, glucocorticoids might be a trophic or permissive factor for pendrin function in ICs. Alternatively, the paradigm of safeguarding aldosterone specificity via the 11-β-HSD2 scavenging system may not apply to the IC-MR. This idea is not farfetched because the ICs express a cell-specific variant of the MR with a regulatory phosphorylation site at position 843 near the steroid hormone binding moiety.⁸ Phosphorylation of S843 precludes binding of aldosterone to the MR, and S843 dephosphorylation is necessary for aldosterone binding.⁸ It is currently not known whether this IC-specific element increases the MR selectivity and thereby, makes the 11-β-HSD2 function superfluous. This would be a highly relevant question for future work. In their newest work, Pham et al.⁵ also report the intriguing finding that IC-specific knockout of the MR triggers a remote effect on ENaC function in the principal cells of the CD. They find that overall ENaC function is markedly reduced in this mouse model. A mechanistic understanding of this observation is currently pending. Interestingly, the data are supported by a similar effect observed in pendrin knockout mice, which also show reduced ENaC function in the CD.⁹ These observations foster the hypothesis that intact β-ICs are a prerequisite for full functionality of the neighboring principal cells. Because these cells are not electrically coupled, IC and principal cells in the CD could potentially use a local communication system to favor proper function of the adjacent cell.^1,10 In summary, our understanding of NaCl handling and regulation in the CD is moving steadily forward toward a more comprehensive model.¹ The role of pendrin as absorptive Cl⁻ transporter in CD becomes clearer and eventually, may offer an alternative target for pharmacologic intervention to increase renal Cl⁻ excretion.

Disclosures

None.