Calcineurin inhibition deactivates pyruvate dehydrogenase and induces proximal tubule cell metabolic dysfunction, causing profibrotic phenotype.

Calcineurin inhibitors (CNIs) are indispensable immunosuppressants for transplant recipients and patients with autoimmune diseases, but chronic use causes nephrotoxicity, including kidney fibrosis. Why inhibiting calcineurin, a serine/threonine phosphatase, causes kidney fibrosis remains unknown. We performed single-nucleus RNA sequencing of the kidney from a chronic CNI nephrotoxicity mouse model and found an increased proportion of injured proximal tubule cells, which exhibited altered expression of genes associated with oxidative phosphorylation, cellular senescence and fibrosis. In cultured primary human renal proximal tubule epithelial cells, CNIs caused phosphorylation (deactivation) of pyruvate dehydrogenase, impaired mitochondrial metabolism and senescence-associated phenotypes, all of which were ameliorated by pyruvate dehydrogenase activation. Finally, administration of dichloroacetic acid, a known activator of pyruvate dehydrogenase, in the chronic CNI nephrotoxicity mouse model mitigated kidney fibrosis and the associated transcriptional changes. Collectively, calcineurin inhibition deactivates pyruvate dehydrogenase and induces proximal tubule cell metabolic dysfunction, causing profibrotic phenotype.