Telomere Dysfunction in Renal Tubular Epithelial Cells Leads to Kidney Fibrosis

Key Points Trf1 deletion in renal tubular epithelial cells led to renal tubulointerstitial fibrosis, contributing to CKD pathogenesis and progression. Loss of Trf1 induced cellular senescence, DNA damage, and telomere shortening and activated regenerative repair. Trf1 deletion triggered kirsten rat sarcoma viral oncogene homolog and TNF- α signaling through NF-κB pathway in renal tubules, suggesting a key molecular mechanism in CKD progression. Background Renal tubular epithelial cells are the critical mediators of kidney fibrogenesis. Telomere dysfunction has been associated with kidney injury and fibrosis. However, the role of telomere dysfunction specifically in renal tubular epithelial cells in the onset and progression of kidney fibrosis remains poorly understood. TRF1 is a critical component of the telomeric protective complex known as shelterin, and its deficiency results in telomere dysfunction. Methods To investigate the impact of telomere dysfunction on kidney injury and fibrosis, we generated mice depleted for the shelterin component TRF1 specifically in renal tubular epithelial cells. Results Genetic ablation of Trf1 caused decline in kidney function accompanied by increased tubular injury and tubulointerstitial fibrosis 8 weeks after TRF1 depletion, concomitant with excessive accumulation of extracellular matrix, cell cycle arrest at G2/M phase, and telomeric damage. Trf1 Δ/Δ mice activated regenerative repair mechanisms, supporting proliferation-mediated telomere shortening in renal tubular epithelial cells. At humane end point, Trf1 Δ/Δ mice displayed elevated urinary albumin-to-creatinine ratio (UACR), associated with augmented interstitial fibrosis and tubular atrophy eventually leading to CKD. At the mechanistic level, we reported the unprecedented finding that Trf1 deletion upregulates the Ras–Raf–Mek–Erk, PI3k/Akt/mammalian target of rapamycin, and p38 pathways. Conclusions Our study underlies a role of renal tubular epithelial cells in the development and progression of kidney fibrosis and CKD induced by telomere dysfunction.