Tenascin C–Derived Peptide 6 Promotes De Novo Kidney Regeneration after Partial Nephrectomy in Axolotl

BACKGROUND: Kidneys possess limited regenerative capacity. While renal tubules are capable of repair following injury, nephron loss resulting from renal mass ablation or disease is irreversible in mammals. In this study, we demonstrated de novo nephron regeneration following partial nephrectomy in axolotls, a model organism renowned for its remarkable regenerative ability. METHODS: Kidney mass ablation was carried out by employing unilateral one-quarter partial nephrectomy in axolotls, and the regeneration process was assessed at multiple time points (0, 1, 2, 4, 8, 12 and 16 weeks) post-surgery. RESULTS: We found that cells migrated into the wound sites and proliferated, beginning at 1 week post-nephrectomy and nearly restoring the cell mass of the contralateral kidney by 4 weeks. Cell proliferation peaked between weeks 2 and 4 at the resected site and was accompanied by fibroblast activation, SOX9 expression and induction of tenascin C. By 16 weeks after nephrectomy, new glomeruli had formed and renal tubules were de novo regenerated and functionally matured. Notably, tenascin C expression was transiently induced, peaking at 2 to 4 weeks post-surgery and rapidly declined as cell repopulation progressed. Knockdown of tenascin C expression reduced cell proliferation and impaired regenerative process. Conversely, administration of tenascin C-derived peptide 6 (TCP6) shifted tenascin C expression to an earlier stage and accelerated both new nephron formation and functional maturation. CONCLUSIONS: These studies demonstrate de novo nephron regeneration following partial nephrectomy in an animal model and identify TCP6 as an accelerator of kidney regeneration in vivo.