NADPH Oxidase 4 and Metabolic Stress in Dahl Salt-Sensitive Rat Kidneys

In SS rats, HS intake upregulated glutaminase and increased glutamate consumption, reflecting a shift toward glutamine-driven metabolism, inefficient oxygen utilization, and elevated ROS. In contrast, SSNOX4⁻/⁻ rats exhibited intrinsically higher NO production and favored fatty acid oxidation (FAO), promoting more efficient oxygen.

Notably, renal lactate release was observed exclusively in SSNOX4⁻/⁻ rats following HS intake, despite no glycolytic gene upregulation, suggesting increased lactate production due to a substrate shift, possibly toward enhanced FAO. Furthermore, SSNOX4⁻/⁻ rats did not exhibit the salt-induced augmentation of amino acid metabolism seen in SS rats, indicating a protein-sparing metabolic adaptation. Together, these findings reveal a distinct metabolic reprogramming in SSNOX4⁻/⁻ rats that enhances energy efficiency and contributes to renal protection under HS conditions.