The Renal Physiology of Pendrin-Positive Intercalated Cells

Abstract

<jats:p> Intercalated cells (ICs) are found in the connecting tubule and the collecting duct. Of the three IC subtypes identified, type B intercalated cells are one of the best characterized and known to mediate Cl<jats:sup>−</jats:sup> absorption and HCO<jats:sub>3</jats:sub><jats:sup>−</jats:sup> secretion, largely through the anion exchanger pendrin. This exchanger is thought to act in tandem with the Na<jats:sup>+</jats:sup>-dependent Cl<jats:sup>−</jats:sup>/HCO<jats:sub>3</jats:sub><jats:sup>−</jats:sup> exchanger, NDCBE, to mediate net NaCl absorption. Pendrin is stimulated by angiotensin II and aldosterone administration via the angiotensin type 1a and the mineralocorticoid receptors, respectively. It is also stimulated in models of metabolic alkalosis, such as with NaHCO<jats:sub>3</jats:sub> administration. In some rodent models, pendrin-mediated HCO<jats:sub>3</jats:sub><jats:sup>−</jats:sup> secretion modulates acid-base balance. However, of probably more physiological or clinical significance is the role of these pendrin-positive ICs in blood pressure regulation, which occurs, at least in part, through pendrin-mediated renal Cl<jats:sup>−</jats:sup> absorption, as well as their effect on the epithelial Na<jats:sup>+</jats:sup> channel, ENaC. Aldosterone stimulates ENaC directly through principal cell mineralocorticoid hormone receptor (ligand) binding and also indirectly through its effect on pendrin expression and function. In so doing, pendrin contributes to the aldosterone pressor response. Pendrin may also modulate blood pressure in part through its action in the adrenal medulla, where it modulates the release of catecholamines, or through an indirect effect on vascular contractile force. In addition to its role in Na<jats:sup>+</jats:sup> and Cl<jats:sup>−</jats:sup> balance, pendrin affects the balance of other ions, such as K<jats:sup>+</jats:sup> and I<jats:sup>−</jats:sup>. This review describes how aldosterone and angiotensin II-induced signaling regulate pendrin and the contribution of pendrin-positive ICs in the kidney to distal nephron function and blood pressure. </jats:p>

Characterization of pendrin in urinary extracellular vesicles in a rat model of aldosterone excess and in human primary aldosteronism

“…Finally, cross-sectional analysis revealed that the pendrin levels in urinary EVs are significantly correlated with ARR. These data are consistent with experimental studies showing the stimulation of pendrin in a state of aldosterone excess, suggesting its role in aldosterone-induced fluid and electrolyte abnormalities [7,10,11,17].…”

“…Excessive production of the steroid hormone aldosterone results in increased activity of NaCl-transporting proteins in renal tubules, thereby increasing fluid volume and blood pressure (BP). Experimental evidence indicates that apical membrane channels and transporters such as the epithelial Na + channel (ENaC), Na-Cl-cotransporter (NCC), and Cl − /HCO 3 − exchanger pendrin are dysregulated under aldosterone excess [6][7][8]. However, few studies have examined whether the reported mechanisms in animal models apply to PA in humans.…”

“…Pendrin, encoded by SLC26A4, is selectively present in β-intercalated cells and non-α, non-β intercalated cells of the kidney, mediating Cl − reabsorption in exchange for HCO 3 − secretion [7]. Experimental studies using animal models have demonstrated the importance of pendrin in regulating BP.…”

The H+-ATPase (V-ATPase): from proton pump to signaling complex in health and disease

“…B-type cells, on the other hand, express a different anion exchanger, pendrin, in their apical membrane, and they lack AE1 ( 110 ). Pendrin-positive cells (which are restricted to the cortex and, to a much lesser extent, the outer stripe of the outer medulla) can express V-ATPase not only in intracellular vesicles but also to different degrees in their apical and/or basolateral membranes ( 111 ). Cells that express apical V-ATPase, but no basolateral AE1, were initially categorized as non-A, non-B cells ( 112 ), and subsequently they were shown to also express apical pendrin alongside the V-ATPase ( 110 ).…”

Urinary Extracellular Vesicles for Renal Tubular Transporters Expression in Patients With Gitelman Syndrome

“…Similarly, downstream ENaCβ in the principal cells of CD for tubular salt reabsorption was enhanced ( 32 , 33 ). Of note, pendrin as a Cl − /HCO3 − exchanger expressed in the apical region of distal tubules and involved in the tubular Cl − absorption and HCO3 − secretion was augmented ( 34 ). Activation of pendrin-mediated Cl − absorption has also been reported in NCC KO mice ( 35 ).…”