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

• DOI: 10.1038/s41467-018-03753-4
• Publication Date: 2018-04-04T02:57:39Z
• Authors: Elena Lazzeri; Maria Lucia Angel...; Anna Peired; Carolina Conte; Julian A. Marschner; Laura Maggi; Benedetta Mazzinghi; Duccio Lombardi; Maria Elena Melica; Sara Nardi; Elisa Ronconi; Alessandro Sisti; Giulia Antonelli; Francesca Becherucci; Letizia De Chiara; Ricardo Romero Gu...; Alexa Burger; Beat Schaefer; Francesco Annunziato; Hans-Joachim Anders; Laura Lasagni; Paola Romagnani
• Keywords: Male; Science; 610 Medicine & health; 1600 General Chemistry; Mice, Transgenic; Cell Enlargement; Article; Mice; PAX8 Transcription Factor; 03 medical and health sciences; 1300 General Biochemistry, Genetics and Molecular Biology; Animals; Humans; Regeneration; Cell Lineage; acute kidney injury, renal progenitors, endocycle, stem cell, renal failure; 0303 health sciences; Ploidies; Q; Cell Cycle; PAX2 Transcription Factor; Epithelial Cells; Acute Kidney Injury; Cell Dedifferentiation; 3100 General Physics and Astronomy; Histone Deacetylase Inhibitors; Mice, Inbred C57BL; Adult Stem Cells; Kidney Tubules; 10036 Medical Clinic; Female

AbstractAcute kidney injury (AKI) is considered largely reversible based on the capacity of surviving tubular cells to dedifferentiate and replace lost cells via cell division. Here we show by tracking individual tubular cells in conditional Pax8/Confetti mice that kidney function is recovered after AKI despite substantial tubular cell loss. Cell cycle and ploidy analysis upon AKI in conditional Pax8/FUCCI2aR mice and human biopsies identify endocycle-mediated hypertrophy of tubular cells. By contrast, a small subset of Pax2+ tubular progenitors enriches via higher stress resistance and clonal expansion and regenerates necrotic tubule segments, a process that can be enhanced by suitable drugs. Thus, renal functional recovery upon AKI involves remnant tubular cell hypertrophy via endocycle and limited progenitor-driven regeneration that can be pharmacologically enhanced.