Kidney Week 2025 Annual Meeting-Aldosterone-Dependent and -Independent Mechanisms in Sodium Transport and Hypertension

Video Transcription

Video Summary

The session opens with announcements about disclosures, recording, evaluations, and CME access, then introduces Dr. Edgar James, who reviews epithelial sodium channel (ENaC) regulation independent of aldosterone. ENaC is a highly sodium-selective, amiloride-sensitive channel composed of alpha, beta, and gamma subunits, expressed prominently in kidney collecting duct principal cells but also in many tissues (lung, colon, vasculature, skin, brain). While aldosterone classically activates ENaC via mineralocorticoid receptor (MR) signaling and SGK1, evidence for aldosterone-independent control includes rapid activation within minutes, persistent activity in MR knockout/aldosterone absence, and ENaC-driven sodium retention in nephrotic syndrome.<br /><br />Dr. James summarizes key aldosterone-independent mechanisms: proteolytic activation (e.g., plasmin in nephrotic syndrome cleaving inhibitory extracellular segments), sodium self-inhibition, chloride allosteric inhibition, acetylation increasing activity (partly by opposing ubiquitination), and ubiquitination via NEDD4-2 as a central regulatory node. He also highlights phosphoinositide (PIP2/PIP3) signaling (notably via insulin/IGF receptors), flow/shear stress mechanotransduction, and rapid trafficking to/from the membrane. Hormonal modulators include insulin (persistent ENaC sensitivity in insulin resistance), vasopressin (V2/cAMP/PKA effects), angiotensin II (AT1/PKC/NOX/ROS), plus multiple inhibitors (NO, endothelin-1 via ETB, ATP, PGE2, bradykinin). He concludes ENaC is an underused drug target (amiloride, protease/PI3K/NOX/NEDD4-2 approaches).<br /><br />Dr. Adet Karaba then discusses immune-cell ENaC and salt-sensitive hypertension, emphasizing rapid BP rises after salt intake, disproportionate prevalence in Black patients, and evidence for extrarenal vascular mechanisms. Her data suggest sodium output may not differ by phenotype, whereas immune activation (myeloid cells) correlates strongly, involving ENaC-related pathways, oxidative stress, inflammasome signaling, cortisol/glucocorticoid receptor effects, and possible lymphatic sodium reservoirs. Subsequent speakers transition to aldosterone-dependent ENaC regulation and primary aldosteronism.

Asset Subtitle

Moderator(s): Ashley Mutchler, David Pollock

Presentation(s):

Epithelial Sodium Channel Regulation Independent of Aldosterone - Edgar Jaimes
Immune Epithelial Sodium Channels and Salt-Sensitive Hypertension - Annet Kirabo
Primary Aldosteronism: An Underdiagnosed Cause of High BP - Jun Yang
Aldosterone-Dependent and -Independent Regulation of Epithelial Sodium Channels in the Kidneys - Lawrence Palmer

Meta Tag

Date 11/8/2025

Pathway 1 Hypertension and Cardiorenal Disorders

Pathway 2 Fluid, Electrolyte, and Acid-Base Disorders

Session ID 507286

Keywords

epithelial sodium channel

ENaC regulation

aldosterone-independent ENaC

collecting duct principal cells

amiloride-sensitive sodium transport

proteolytic ENaC activation

plasmin nephrotic syndrome

NEDD4-2 ubiquitination

SGK1 mineralocorticoid receptor signaling

PIP2 PIP3 PI3K signaling

insulin IGF ENaC activation

vasopressin V2 cAMP PKA

angiotensin II AT1 PKC NOX ROS

immune cell ENaC

salt-sensitive hypertension