4.5 Article

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

Journal

HYPERTENSION RESEARCH
Volume 44, Issue 12, Pages 1557-1567

Publisher

SPRINGERNATURE
DOI: 10.1038/s41440-021-00710-5

Keywords

Mineralocorticoid; Transporter; Urine; Exosome

Funding

  1. JSPS KAKENHI [19H03678, 19K22643]
  2. Uehara Memorial Foundation
  3. Grants-in-Aid for Scientific Research [19K22643, 19H03678] Funding Source: KAKEN

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The study demonstrates the correlation between pendrin levels in uEVs and human PA, suggesting that therapeutic interventions can attenuate pendrin abundance in patients with PA. The analysis of pendrin in uEVs, along with other proteins, may be useful in understanding the pathophysiology of hypertensive disorders.
Pendrin is a Cl-/HCO3- exchanger selectively present in the intercalated cells of the kidney. Although experimental studies have demonstrated that pendrin regulates blood pressure downstream of the renin-angiotensin-aldosterone system, its role in human hypertension remains unclear. Here, we analyzed the quantitative changes in pendrin in urinary extracellular vesicles (uEVs) isolated from a total of 30 patients with primary aldosteronism (PA) and from a rat model of aldosterone excess. Western blot analysis revealed that pendrin is present in dimeric and monomeric forms in uEVs in humans and rats. In a rodent model that received continuous infusion of aldosterone with or without concomitant administration of the selective mineralocorticoid receptor (MR) antagonist esaxerenone, pendrin levels in uEVs, as well as those of epithelial Na+ channel (ENaC) and Na-Cl-cotransporter (NCC), were highly correlated with renal abundance. In patients with PA, pendrin levels in uEVs were reduced by 49% from baseline by adrenalectomy or pharmacological MR blockade. Correlation analysis revealed that the magnitude of pendrin reduction after treatment significantly correlated with the baseline aldosterone-renin ratio (ARR). Finally, a cross-sectional analysis of patients with PA confirmed a significant correlation between the ARR and pendrin levels in uEVs. These data are consistent with experimental studies showing the role of pendrin in aldosterone excess and suggest that pendrin abundance is attenuated by therapeutic interventions in human PA. Our study also indicates that pendrin analysis in uEVs, along with other proteins, can be useful to understand the pathophysiology of hypertensive disorders.

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