Tubular Metabolism in Kidney Disease

Tubular Metabolism in CKD

• Recent studies have explored metabolic alterations in various forms of chronic kidney disease (CKD).
• Metabolic reprogramming is central to the pathophysiology of CKD, with alterations in glucose and fatty acid metabolism occurring early in the course of diabetic and other forms of CKD.

Glucose Metabolism in CKD

• Defective glucose metabolism, specifically increased aerobic glycolysis, was observed in mouse models of autosomal dominant polycystic kidney disease (ADPKD) and in kidney tissue from patients with ADPKD.
• Treatment with 2-deoxyglucose, an inhibitor of glycolysis, lowered kidney weight, volume, cystic index, and proliferation rates in mouse models of ADPKD.
• The Warburg effect, characterized by enhanced aerobic glycolysis, is typically seen in proliferating cancer cells.

Fatty Acid Metabolism in CKD

• Changes in fatty acid metabolism in the kidney have been described in CKD, with reduced levels of enzymes and regulators involved in fatty acid oxidation in mouse models of fibrosis.
• Genes related to fatty acid metabolism and their key transcriptional regulator complex, PPARA–PPARGC1A, were markedly lower in CKD samples compared with samples from people with normal kidney function.
• Lipid accumulation in renal tubular epithelial cells was higher in CKD samples.

Metabolic Reprogramming in Diabetic CKD

• Proximal tubules are largely dependent on mitochondrial oxidative metabolism for energy with limited glycolytic capacity.
• In diabetes, there are increases in plasma concentration of glucose and fatty acids, which are also found intracellularly in the kidneys, particularly proximal tubules.
• Increased renal metabolism is associated with increased protein acetylation, a nutrient sensing posttranslational modification.
• Mitochondrial dysfunction is also evident in diabetic CKD.

Metabolic Alterations in Diabetic Nephropathy

• Transcriptomic and metabolomic profiling in a type 2 diabetic mouse model demonstrated an increase in glycolysis, fatty acid β-oxidation, and tricarboxylic acid (TCA) cycle flux.
• Urine samples from diabetic patients showed increased glycolytic and TCA cycle metabolites compared with healthy control subjects.
• TCA cycle intermediates in the urine were elevated in diabetic subjects and predicted diabetic kidney disease progression, demonstrating their potential as prognostic biomarkers.