Revisiting voltage-coupled H⁺ secretion in the collecting duct

Area of Science:

• Nephrology
• Physiology
• Molecular Biology

Background:

• The
• voltage hypothesis
• proposes that V-type ATPase-driven H⁺ secretion in the kidney collecting duct is enhanced by a lumen-negative potential created by Na⁺ reabsorption through the epithelial Na⁺ channel (ENaC).
• This concept is foundational in understanding acid-base disorders.

Purpose of the Study:

• To critically evaluate the evidence supporting the voltage hypothesis in physiologically relevant contexts.
• To explore recent findings that challenge the direct applicability of voltage-coupled H⁺ secretion in the collecting duct.

Main Methods:

• Review of experimental studies on V-type ATPase function and transepithelial voltage.
• Analysis of in vivo functional studies investigating collecting duct acidification.
• Examination of the relationship between ENaC function and H⁺ secretion.

Main Results:

• Direct proof of principle for the voltage hypothesis in vivo is lacking.
• Recent in vivo studies challenge the hypothesis's applicability.
• The proposed link between ENaC activity and H⁺ secretion may not consistently explain changes in acid-base balance.

Conclusions:

• The voltage hypothesis, while widely cited, may not accurately reflect the complex regulation of urinary acidification.
• Alternative mechanisms or a revised understanding of voltage coupling are needed to explain H⁺ secretion in the collecting duct.
• The direct correlation between ENaC function and H⁺ secretion is questionable in physiological conditions.