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

key pointsDe novo nephron regeneration was achieved after partial nephrectomy in axolotls. Tenascin C induction peaked at 2-4 weeks postpartial nephrectomy and coincided with cell proliferation and extracellular matrix remodeling. Tenascin C-derived peptide 6, a tenascin C-derived matrikine, accelerated kidney regeneration by enhancing extracellular matrix remodeling and tenascin C expression.

backgroundKidneys possess limited regenerative capacity. While renal tubules are capable of repair after injury, nephron loss resulting from renal mass ablation or disease is irreversible in mammals. In this study, we demonstrated de novo nephron regeneration after partial nephrectomy in axolotls, a model organism renowned for its remarkable regenerative ability.

methodsKidney mass ablation was performed by using 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) postsurgery.

resultsWe found that cells migrated into the wound sites and proliferated, beginning at 1 week postnephrectomy 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 2-4 weeks postsurgery 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 shifted tenascin C expression to an earlier stage and accelerated both new nephron formation and functional maturation.

conclusionsThese studies demonstrate de novo nephron regeneration after partial nephrectomy in an animal model and identify tenascin C-derived peptide 6 as an accelerator of kidney regeneration in vivo .