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

• Published in: Nature communications Vol. 9; no. 1; pp. 1344 - 18
• Main Authors: Lazzeri, Elena, Angelotti, Maria Lucia, Peired, Anna, Conte, Carolina, Marschner, Julian A., Maggi, Laura, Mazzinghi, Benedetta, Lombardi, Duccio, Melica, Maria Elena, Nardi, Sara, Ronconi, Elisa, Sisti, Alessandro, Antonelli, Giulia, Becherucci, Francesca, De Chiara, Letizia, Guevara, Ricardo Romero, Burger, Alexa, Schaefer, Beat, Annunziato, Francesco, Anders, Hans-Joachim, Lasagni, Laura, Romagnani, Paola
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 09.04.2018; Nature Publishing Group; Nature Portfolio
• Subjects: 13/31; 13/51; 14/1; 14/19; 14/32; 14/63; 45/77; 631/532/489; 64/60; 692/4022/1585/4; Acute Kidney Injury - genetics; Acute Kidney Injury - pathology; Acute Kidney Injury - physiopathology; Adult Stem Cells - pathology; Animals; Cell Cycle; Cell Dedifferentiation; Cell division; Cell Enlargement; Cell Lineage; Epithelial Cells - drug effects; Epithelial Cells - pathology; Female; Histone Deacetylase Inhibitors - pharmacology; Humanities and Social Sciences; Humans; Hypertrophy; Kidney Tubules - drug effects; Kidney Tubules - pathology; Kidney Tubules - physiopathology; Kidneys; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; multidisciplinary; Pax2 protein; PAX2 Transcription Factor - metabolism; Pax8 protein; PAX8 Transcription Factor - metabolism; Pharmacology; Ploidies; Ploidy; Recovery of function; Regeneration; Regeneration - drug effects; Renal function; Science; Science (multidisciplinary); Single-Cell Analysis
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-03753-4

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. 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. The recovery of function upon acute kidney injury is thought to involve tubular cell dedifferentiation and proliferation. Here the authors show that Pax2+ progenitors regenerate tubules via cell division while other tubular cells support function recovery by undergoing hypertrophy through endoreplication.