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Review
. 2016 Feb 15;310(4):C243-59.
doi: 10.1152/ajpcell.00328.2015. Epub 2015 Dec 2.

An unexpected journey: conceptual evolution of mechanoregulated potassium transport in the distal nephron

Rolando Carrisoza-Gaytan  1 , Marcelo D Carattino  2 , Thomas R Kleyman  2 , Lisa M Satlin  3
Affiliations
Review

An unexpected journey: conceptual evolution of mechanoregulated potassium transport in the distal nephron

Rolando Carrisoza-Gaytan et al. Am J Physiol Cell Physiol. .

Abstract

Flow-induced K secretion (FIKS) in the aldosterone-sensitive distal nephron (ASDN) is mediated by large-conductance, Ca(2+)/stretch-activated BK channels composed of pore-forming α-subunits (BKα) and accessory β-subunits. This channel also plays a critical role in the renal adaptation to dietary K loading. Within the ASDN, the cortical collecting duct (CCD) is a major site for the final renal regulation of K homeostasis. Principal cells in the ASDN possess a single apical cilium whereas the surfaces of adjacent intercalated cells, devoid of cilia, are decorated with abundant microvilli and microplicae. Increases in tubular (urinary) flow rate, induced by volume expansion, diuretics, or a high K diet, subject CCD cells to hydrodynamic forces (fluid shear stress, circumferential stretch, and drag/torque on apical cilia and presumably microvilli/microplicae) that are transduced into increases in principal (PC) and intercalated (IC) cell cytoplasmic Ca(2+) concentration that activate apical voltage-, stretch- and Ca(2+)-activated BK channels, which mediate FIKS. This review summarizes studies by ourselves and others that have led to the evolving picture that the BK channel is localized in a macromolecular complex at the apical membrane, composed of mechanosensitive apical Ca(2+) channels and a variety of kinases/phosphatases as well as other signaling molecules anchored to the cytoskeleton, and that an increase in tubular fluid flow rate leads to IC- and PC-specific responses determined, in large part, by the cell-specific composition of the BK channels.

Keywords: WNK kinases; cilia; kidney; mechanoregulation; potassium transport.

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Figures

Fig. 1.
Fig. 1.
Flow stimulation of net K secretion (left) and Na absorption (right) in the maturing rabbit CCD. Net transport was measured at slow (∼1 nl·min−1·mm−1), moderate (∼2 nl·min−1·mm−1), and fast (∼5 nl·min−1·mm−1) flow rates in tubules isolated from 2-, 4-, and 6-wk-old rabbits (n = 5–6 per age group) and microperfused in vitro. Net K secretion was absent at 2 wk of age and could not be stimulated by an increase in tubular fluid flow rate. Although a 5-fold increase in flow rate stimulated net Na absorption at 4 wk to levels comparable to those observed at 6 wk of age, no flow-induced increase in net K secretion (FIKS) was detected at 1 mo of life in response to an increase in flow rate to 5 nl·min−1·mm−1. Weaning occurs in the rabbit by 4 wk of age. FIKS was clearly evident by 6 wk of age. [Adapted from Satlin (173) and Woda et al. (237).]
Fig. 2.
Fig. 2.
Cell-specific mechanoregulation of BK channel-mediated K secretion in the CCD. BK channels, present in principal cell cilia and at the apical membranes of both principal (A and B) and intercalated (C and D, E and F) cells in the CCD, are closed at slow physiologic flow rates (A, C, and E). An increase in tubular flow rate (B, D, and F) induces BK channel-mediated K secretion (FIKS), which requires ENaC-mediated apical Na entry, an increase in intracellular Ca2+ concentration (reflecting internal store release and Ca2+ entry into cells), and basolateral NKCC1 activity. Emerging evidence indicates that BK channel activity in this nephron segment is regulated by autocrine/paracrine factors released into the tubular fluid as well as cell-specific macromolecular complexes that include kinase signaling. Note that we do not know as yet whether principal or intercalated cells mediate FIKS. See manuscript for details.
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