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

Abstract

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.

Regulation of Blood Pressure and Salt Balance By Pendrin-Positive Intercalated Cells: Donald Seldin Lecture 2020

“…In the mouse, apical plasma membrane pendrin abundance is low under basal conditions but increases ≈6-fold in response to aldosterone. 11 Ochiai-Homma et al 87 quantified pendrin abundance in human urinary extracellular vesicles as an index of renal pendrin abundance and showed that aldosterone upregulates pendrin in human kidney, consistent with observations in mouse. Moreover, they showed a strong correlation between pendrin abundance in these human urinary extracellular vesicles and serum aldosterone concentration.…”

“…87 Following either adrenalectomy or MR antagonist administration, pendrin abundance in urinary vesicles fell substantially. 87 Therefore, in rodents and in humans, aldosterone greatly stimulates pendrin abundance in the kidney, which occurs, at least partly, through the alkalosis it generates. 88 Aldosterone increases apical plasma membrane pendrin expression in tandem with increased pendrin-mediated Cl − absorption and HCO 3 − secretion.…”

“…Moreover, they showed a strong correlation between pendrin abundance in these human urinary extracellular vesicles and serum aldosterone concentration. 87 Following either adrenalectomy or MR antagonist administration, pendrin abundance in urinary vesicles fell substantially. 87 Therefore, in rodents and in humans, aldosterone greatly stimulates pendrin abundance in the kidney, which occurs, at least partly, through the alkalosis it generates.…”

Update on Hypertension Research in 2021

“…Exosomes may serve as biomarkers of MR activity. Ochiai-Homma et al [ 159 ] focused on pendrin, a Cl – /HCO3 – exchanger that is only expressed by renal intercalated cells. In a rat model, the pendrin level in the urinary exosome was reduced by therapeutic interventions favored for PA patients; the urinary level was correlated with the renal level.…”

Exosomes as Intercellular Messengers in Hypertension

“…Interestingly, the literature has demonstrated a role for exosomes in physiological and pathological conditions, such as in the progression of cancer, which has been vastly described in the literature [ 17 , 18 , 19 , 20 ]. In addition, circulating and urinary exosomes are being used to identify key proteins and microRNA (miRNAs), circular RNAs (circRNA), or long non-coding RNA (lncRNA) associated with different diseases including type 2 diabetes, nephropathy, aldosteronism, atherosclerosis, and several types of cancer (bladder, gastric, prostate cancers) [ 21 , 22 , 23 , 24 , 25 ]. Therefore, it seems that the exosomes carry potential molecules to help in the diagnosis of diseases.…”