Metabolic Dynamics in Kidney Disease

Kidney disease is increasingly recognised as a disorder of cellular energy management, in which renal cells undergo profound shifts in fuel utilisation and signalling pathways. Under healthy conditions, proximal tubular epithelial cells depend primarily on fatty acid oxidation to meet high adenosine triphosphate demands. Following injury, whether acute or chronic, there is a coordinated suppression of mitochondrial and peroxisomal lipid catabolism and a compensatory rise in glycolytic flux. This reprogramming supports cell survival but also drives maladaptive processes, including epithelial dedifferentiation, myofibroblast activation and extracellular matrix deposition. Central regulators of these shifts include nutrient-sensitive kinases and transcription factors that govern lipid transport, mitochondrial biogenesis and autophagy. Disordered metabolic dynamics contribute to persistent inflammation, fibrogenesis and progressive loss of renal function. New insights into signalling nodes and metabolic enzymes offer therapeutic opportunities to restore energy balance, limit fibrotic remodelling and preserve kidney architecture worldwide.

Research from Nature Portfolio

Recent studies have identified the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) as a pivotal driver of chronic kidney disease progression via metabolic reprogramming. Elevated DNA-PKcs in injured epithelial cells and myofibroblasts enhances mTORC1 activation through upregulation of regulatory associated protein of mTOR (RAPTOR) via the transcription factor TAF7. Genetic ablation or pharmacological inhibition of DNA-PKcs preserves epithelial phenotype, suppresses fibroblast activation and corrects the pathological shift from fatty acid oxidation to glycolysis. These findings position DNA-PKcs as a promising target for interventions aiming to recalibrate metabolic signalling in renal fibrosis.

Metabolic Dynamics in Kidney Disease publication trend

The graph below shows the total number of articles in metabolic dynamics in kidney disease across all publications each year (not limited to Nature Index journals).

Technical terms

Fatty acid oxidation (FAO): Metabolic pathway in mitochondria and peroxisomes converting fatty acids into acetyl-CoA to generate ATP.

Glycolysis: Cytosolic process that breaks down glucose into pyruvate or lactate, yielding rapid but less efficient ATP production.

Myofibroblast activation: Transformation of epithelial cells or resident fibroblasts into collagen-producing, contractile cells driving fibrosis.

mTORC1 signalling: Nutrient-sensitive kinase complex that regulates cell growth, protein synthesis and metabolism in response to environmental cues.

Peroxisome proliferator-activated receptor α (PPARα): Nuclear receptor that controls the expression of genes involved in fatty acid uptake and oxidation.

Liquid–liquid phase separation (LLPS): Process by which disordered protein regions form dynamic biomolecular condensates to enhance transcriptional activity.

Klotho: Anti-aging transmembrane protein produced by tubular cells that modulates multiple signalling pathways, including PPARα-mediated lipid metabolism.

References

1. DNA-dependent protein kinase catalytic subunit (DNA-PKcs) drives chronic kidney disease progression in male mice. Nature Communications (2023).
2. ACOT12, a novel factor in the pathogenesis of kidney fibrosis, modulates ACBD5. Experimental & Molecular Medicine (2025).
3. Forkhead Box Protein K1 Promotes Chronic Kidney Disease by Driving Glycolysis in Tubular Epithelial Cells. Advanced Science (2024).
4. Nanoparticle-mediated Klotho gene therapy prevents acute kidney injury to chronic kidney disease transition through regulating PPARα signaling in renal tubular epithelial cells. Biomaterials (2024).
5. Sugar or Fat? Renal Tubular Metabolism Reviewed in Health and Disease. Nutrients (2021).