Pyruvate Dehydrogenase and Cellular Metabolism in Calcineurin Inhibitor-Induced Kidney Fibrosis

Area of Science:

• Nephrology
• Immunology
• Molecular Biology

Background:

• Calcineurin inhibitors (CNIs) are vital immunosuppressants for transplant recipients and autoimmune disease patients.
• Chronic CNI use leads to nephrotoxicity and kidney fibrosis, but the underlying mechanisms remain unclear.

Purpose of the Study:

• To investigate the early cellular and molecular changes in chronic CNI nephrotoxicity using single-cell resolution.
• To elucidate the role of metabolic dysfunction in CNI-induced kidney fibrosis.

Main Methods:

• Single-nucleus RNA sequencing (snRNA-seq) of mouse kidneys under chronic CNI treatment.
• In vitro studies using primary human renal proximal tubule epithelial cells exposed to CNIs.
• Pharmacological intervention with a pyruvate dehydrogenase activator in a mouse model.

Main Results:

• snRNA-seq revealed increased proximal tubule cell injury, senescence, and fibrosis gene expression.
• CNIs impaired mitochondrial metabolism and induced senescence in human renal cells by deactivating pyruvate dehydrogenase.
• Pyruvate dehydrogenase activation ameliorated CNI-induced metabolic dysfunction, senescence, and kidney fibrosis in mice.

Conclusions:

• CNI-induced nephrotoxicity involves pyruvate dehydrogenase deactivation and proximal tubule cell metabolic dysfunction.
• Metabolic dysfunction in proximal tubule cells is an early hallmark of chronic CNI nephrotoxicity.
• Targeting pyruvate dehydrogenase offers a potential therapeutic strategy against CNI-induced kidney fibrosis.