Hyperuricemia increases susceptibility to chronic kidney injury exacerbation via autophagic flux blockade-mediated ammonia death pathway

Abstract

Introduction: Ammonia (NH3), a core toxic byproduct of amino acid metabolism in the body, poses a severe threat to cell survival when its homeostasis is disrupted. Maintaining low systemic ammonia concentrations is crucial. Under physiological conditions, the kidneys regulate ammonia metabolism precisely through glutaminase (GLS1)- mediated ammonia production and the urea cycle, ensuring efficient detoxification. Hyperuricemic nephropathy (HN), a common complication of hyperuricemia, impairs patient health significantly. However, whether and how ammonia toxicity triggers cell death under this pathological condition remains unclear.

Objectives: This study aimed to investigate whether ammonia-dependent cell death occurs in HN and to elucidate the underlying molecular mechanisms, focusing on the role of ammonia metabolism disorder and autophagic flux blockade.

Methods: We employed both in vivo and in vivo models of HN. Cellular and tissue damage were assessed by ultrastructural analysis, fluorescent probes for reactive oxygen species and mitochondrial membrane potential, and autophagic flux detection. Causal relationships were verified using ammonia scavengers and gene intervention.

Results: Chronic hyperuricemic stress accelerated renal glutaminolysis to maintain ATP supply, leading to excessive mitochondrial ammonia production. Accumulated ammonia underwent RHCG-dependent transmembrane transport, causing lysosomal alkalinization and dysfunction, which in turn promoted mitochondrial ammonia retention and swelling. This process inhibited autolysosomal disassembly, impaired clearance of damaged mitochondria, and blocked autophagic flux, ultimately driving cell death.

Conclusion: Our findings identified a distinct form of cell death in HN, mechanistically divergent from previously known mechanisms such as apoptosis or pyroptosis. It redefined HN pathogenesis through a metabolic lens, identifying druggable targets to mitigate renal damage in hyperuricemic patients.