Oxidative stress-induced NCC activation in the development of nocturnal polyuria in mice: Therapeutic potential of a sustained hydrogen-releasing silicon-based agent

Abstract

Nocturnal polyuria is a prevalent condition associated with significant deterioration in quality of life and increased risk of mortality. Despite its clinical relevance, the underlying pathogenesis is poorly understood, and existing therapies have limited efficacy. A recent study in mouse model revealed that overactivation of the intrarenal SPAK (STE20/SPS1-related proline–alanine rich protein kinase)–sodium chloride co-transporter (NCC) pathway in the distal renal tubule is a crucial mechanism contributing to nocturnal polyuria. Here, we demonstrate that increased oxidative stress in the kidney activates the NCC, leading to insufficient sodium excretion during the active period and compensatory sodium excretion during the inactive period, resulting in polyuria during the inactive period. In addition, we show that a newly developed antioxidant—a silicon component agent—reduced oxidative stress and inhibited NCC activation, resulting in the amelioration of polyuria during the inactive period. These findings highlight the critical contributions of intrarenal oxidative stress to the pathogenesis of nocturnal polyuria and suggest that silicon-based agent holds promise for clinical application as a novel treatment for nocturnal polyuria.