Clusterin elaborated by renal tubular epithelial cells under high oxalate stress serves as a matrix protein to facilitate kidney stone formation

Calcium oxalate (CaOx) kidney stone is prevalent while the molecular mechanisms are not yet fully understood. The organic matrix of stones is rich in protein and has been considered to play a important role in stone aggregation and growth. Through multi-omics approaches, we identified that renal tubular epithelial cell (RTECs)-derived clusterin (CLU), as a matrix protein, promotes renal CaOx stone formation. Proteomics revealed significant enrichment of CLU in CaOx stones. Transcriptomic and single-cell transcriptome data from human kidney specimens confirmed marked upregulation of CLU in RTECs of kidney stone patients. In vitro, CLU accelerated renal CaOx crystal growth. Specifically, conditionally knock out of CLU in RTECs significantly alleviated CaOx crystal deposition in mouse kidneys. Furthermore, hyperoxaluria upregulated CLU in RTECs via the TGF-β1-SMAD2/3-Twist1 pathway, thereby facilitating stone formation. Our study highlights the role of the TWIST1-CLU regulatory axis in renal CaOx stone formation, suggesting CLU as a potential therapeutic target for CaOx kidney stones.