Pendrin localizes to the adrenal medulla and modulates catecholamine release

Lazo‐Fernandez, Yoskaly; Aguilera, Greti; Pham, Truyen D.; Park, Annie Y.; Beierwaltes, William H.; Sutliff, Roy L.; Verlander, Jill W.; Pacák, Karel; Osunkoya, Adeboye O.; Ellis, Carla LaShannon; Kim, Young Hee; Shipley, Gregory L.; Wynne, Brandi M.; Hoover, Robert S.; Sen, Shurjo K.; Plotsky, Paul M.; Wall, Susan M.

doi:10.1152/ajpendo.00035.2015

Cited by 22 publications

(33 citation statements)

References 41 publications

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“…Recently, it was demonstrated that severe dietary NaCl restriction in mice causes only a 33% increase in pendrin protein abundance in renal homogenates (Lazo‐Fernandez et al . ). With moderate dietary NaCl restriction (0.13 mequiv Na + per day), apical plasma membrane pendrin abundance in type B intercalated cells doubles, although total pendrin protein abundance per cell is unchanged.…”

Section: Discussionmentioning

confidence: 97%

The chloride–bicarbonate exchanger pendrin is increased in the kidney of the pregnant rat

West

Verlander

Wall

et al. 2015

Experimental Physiology

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New Findings r What is the central question of this study?Pregnancy requires a robust plasma volume expansion driven by renal sodium retention. In the late-pregnant kidney, the aldosterone-responsive epithelial Na + channel is increased, whereas the sodium-chloride cotransporter is decreased. Pendrin has been shown to support sodium reabsorption in the distal nephron and compensate for loss of the sodium-chloride cotransporter. We investigated the expression and abundance of pendrin in the pregnant kidney. r What is the main finding and its importance?Pendrin protein, apical localization and thiazide sensitivity are increased in pregnancy. This implicates a possible role for pendrin in supporting the renal sodium chloride reabsorption and plasma volume expansion of pregnancy.Pregnancy is characterized by cumulative plasma volume expansion as a result of renal sodium retention, driven by activation of aldosterone. We previously reported that the abundance and activity of the aldosterone-responsive epithelial Na + channel is increased, whereas the sodium-chloride cotransporter (NCC) is decreased in the kidney of the late-pregnant rat. The chloride-bicarbonate exchanger pendrin is also aldosterone responsive and has been shown to support activity of the aldosterone-responsive epithelial Na + channel and compensate for the loss of NCC. Additionally, pendrin coupled to the sodium-dependent chloride-bicarbonate exchanger (NDCBE) mediates thiazide-sensitive sodium reabsorption in the cortical collecting duct. In this study, we investigated pendrin and NDCBE transcript expression, pendrin protein abundance, pendrin cellular localization and thiazide sensitivity in virgin, mid-pregnant and late-pregnant rats to test the hypothesis that increased pendrin activity might occur in pregnancy. By RT-PCR, NDCBE and pendrin mRNA expression was unchanged from virgins, whereas pendrin protein abundance determined by Western blotting was increased in both mid-and late-pregnant rats. The apical localization of pendrin was also increased in late-pregnant rats compared with virgins by immunohistochemistry. Pregnant rats displayed an increased natriuretic response to hydrochlorothiazide compared with virgins. Given that NCC expression is decreased in late pregnancy, an increased thiazide sensitivity may be due to inhibition of upregulated pendrin-NDCBE-coupled sodium reabsorption. Thus, increased pendrin in pregnant rats may compensate for the decreased NCC and aid in the renal sodium chloride reabsorption of pregnancy.

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Section: Discussionmentioning

confidence: 97%

The chloride–bicarbonate exchanger pendrin is increased in the kidney of the pregnant rat

West

Verlander

Wall

et al. 2015

Experimental Physiology

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“…Whether pendrin protein is expressed in neural tissue is unexplored. However, pendrin is expressed in epinephrine-and norepinephrine-producing chromaffin cells within the rodent adrenal medulla, where it modulates catecholamine release (36). Although basal levels of plasma epinephrine and norepinephrine concentrations are similar in wild-type and pendrin null mice, the concentration of both of these catecholamines is higher in pendrin null than in wild-type mice after 20 min of immobilization stress.…”

Section: Does Pendrin Modulate Blood Pressure Solely Through Its Actimentioning

confidence: 99%

The role of pendrin in blood pressure regulation

Wall

2016

American Journal of Physiology-Renal Physiology

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Pendrin is a Na(+)-independent Cl(-)/HCO3(-) exchanger found in the apical regions of type B and non-A, non-B intercalated cells within the aldosterone-sensitive region of the nephron, i.e., the distal convoluted tubule (DCT), the connecting tubule (CNT), and the cortical collecting duct (CCD). Type B intercalated cells mediate Cl(-) absorption and HCO3(-) secretion primarily through pendrin-mediated Cl(-)/HCO3(-) exchange. This exchanger is upregulated with angiotensin II administration and in models of metabolic alkalosis, such as following administration of aldosterone or NaHCO3. In the absence of pendrin-mediated HCO3(-) secretion, an enhanced alkalosis is observed following aldosterone or NaHCO3 administration. However, probably of more significance is the role of pendrin in the pressor response to aldosterone. Pendrin mediates Cl(-) absorption and modulates aldosterone-induced Na(+) absorption mediated by the epithelial Na channel (ENaC). Pendrin changes ENaC activity by changing both channel open probability (Po) and surface density (N), at least partly by altering luminal HCO3(-) and ATP concentration. Thus aldosterone and angiotensin II stimulate pendrin expression and function, which stimulates ENaC activity, thereby contributing to the pressor response of these hormones. However, pendrin may modulate blood pressure partly through its extrarenal effects. For example, pendrin is expressed in the adrenal medulla, where it modulates catecholamine release. The increase in catecholamine release observed with pendrin gene ablation likely contributes to the increment in vascular contractile force observed in the pendrin null mouse. This review summarizes the signaling mechanisms that regulate pendrin abundance and function as well as the contribution of pendrin to distal nephron function.

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“…Functional studies show that pendrin mediates electroneutral exchange of Cl 2 with various anions including I 2 , HCO 3 2 , OH 2 , NO 3 2 , SCN 2 (thiocyanate), and HCO 2 2 (formate) (2)(3)(4)(5)(6)(7)(8). In addition to the inner ear and thyroid, pendrin is expressed in the kidney, airways, and adrenal gland (1,4,6,7,(9)(10)(11)(12).…”

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Inhibitors of pendrin anion exchange identified in a small molecule screen increase airway surface liquid volume in cystic fibrosis

Haggie

Phuan²,

Tan³

et al. 2016

FASEB j.

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Pendrin (SLC26A4) is a Cl 2 /anion exchanger expressed in the epithelium of inflamed airways where it is thought to facilitate Cl 2 absorption and HCO 3 2 secretion. Studies using pendrin knockout mice and airway epithelial cells from hearing-impaired subjects with pendrin loss of function suggest involvement of pendrin in inflammatory lung diseases, including cystic fibrosis (CF), perhaps by regulation of airway surface liquid (ASL) volume. Here we identified small-molecule pendrin inhibitors and demonstrated their efficacy in increasing ASL volume. A cell-based, functional high-throughput screen of ∼36,000 synthetic small molecules produced 3 chemical classes of inhibitors of human pendrin. After structure-activity studies, tetrahydropyrazolopyridine and pyrazolothiophenesulfonamide compounds reversibly inhibited pendrin-facilitated Cl 2 exchange with SCN 2 , I 2 , NO 3 2 , and HCO 3 2 with drug concentration causing 50% inhibition down to ∼2.5 mM. In well-differentiated primary cultures of human airway epithelial cells from non-CF and CF subjects, treatment with IL-13, which causes inflammation with strong pendrin up-regulation, strongly increased Cl 2 /HCO 3 2 exchange and the increase was blocked by pendrin inhibition. Pendrin inhibition significantly increased ASL depth (by ∼8 mm) in IL-13-treated non-CF and CF cells but not in untreated cells. These studies implicate the involvement of pendrin-facilitated Cl 2 / HCO 3 2 in the regulation of ASL volume and suggest the utility of pendrin inhibitors in inflammatory lung diseases, including CF

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Pendrin localizes to the adrenal medulla and modulates catecholamine release

Cited by 22 publications

References 41 publications

The chloride–bicarbonate exchanger pendrin is increased in the kidney of the pregnant rat

The chloride–bicarbonate exchanger pendrin is increased in the kidney of the pregnant rat

The role of pendrin in blood pressure regulation

Inhibitors of pendrin anion exchange identified in a small molecule screen increase airway surface liquid volume in cystic fibrosis

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