Energy Metabolism Dysregulation in Chronic Kidney Disease

KEY POINTS: There is significant enrichment in metabolic pathways in early stages in the subtotal nephrectomy model of CKD. Proximal tubular mitochondrial respiration is suppressed likely from mitochondrial dysfunction in substrate utilization and ATP synthesis. There is significant suppression of pyruvate dehydrogenase and increased glycolysis in proximal tubules. BACKGROUND: CKD is a significant contributor to morbidity and mortality. A better understanding of mechanisms underlying CKD progression is indispensable for developing effective therapies. Toward this goal, we addressed specific gaps in knowledge regarding tubular metabolism in the pathogenesis of CKD using the subtotal nephrectomy (STN) model in mice. METHODS: Weight- and age‐matched male 129X1/SvJ mice underwent sham or STN surgeries. We conducted serial GFR and hemodynamic measurements up to 16 weeks after sham and STN surgery and established the 4-week time point for subsequent studies. RESULTS: For a comprehensive assessment of renal metabolism, we conducted transcriptomic analyses, which showed significant enrichment of pathways involved in fatty acid metabolism, gluconeogenesis, glycolysis, and mitochondrial metabolism in STN kidneys. Expression of rate-limiting fatty acid oxidation and glycolytic enzymes was increased in STN kidneys, and proximal tubules in STN kidneys exhibited increased functional glycolysis but decreased mitochondrial respiration, despite an increase in mitochondrial biogenesis. Assessment of the pyruvate dehydrogenase complex pathway showed significant suppression of pyruvate dehydrogenase, suggesting decreased provision of acetyl CoA from pyruvate for the citric acid cycle to fuel mitochondrial respiration. CONCLUSION: Metabolic pathways are significantly altered in response to kidney injury and may play an important role in the disease progression.