Endocycle-related tubular cell hypertrophy and progenitor proliferation recover renal function after acute kidney injury.

Acute kidney injury (AKI) is considered largely reversible based on the capacity of surviving tubular cells to dedifferentiate and replace lost cells via cell division. However, tracking individual tubular cells in conditional Pax8/Confetti mice with AKI reveals recovery of function despite substantial tubular cell loss. Clonal analysis argues against a stochastic tubular cell proliferation as indicated by proliferation markers rather indicating cell cycle activation than cell division. Cell-cycle and ploidy analysis upon AKI in conditional Pax8/FUCCI2aR mice and human biopsies rather identify endocycle-mediated hypertrophy of tubular cells. By contrast, a small subset of Pax2+ tubular progenitors gets enriched via higher stress resistance and clonal expansion, regenerating necrotic tubule segments. Drugs enhancing tubular regeneration do so only via increasing progenitor mitosis. These results challenge the current paradigms and demonstrate that renal functional recovery upon AKI involves remnant tubular cell hypertrophy via endocycle and limited progenitor-driven regeneration that can be pharmacologically enhanced.