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

Elena Lazzeri,Beat Schaefer,Duccio Lombardi,Francesco Annunziato,Elisa Ronconi,Carolina Conte,Giulia Antonelli,Letizia De Chiara,Hans‐Joachim Anders ,Benedetta Mazzinghi,Ricardo Romero-Guevara ,Laura Lasagni,Anna Julie Peired ,Laura Maggi,S Nardi ,Francesca Becherucci,Julian A Marschner,Maria Elena Melica,Alessandro Sisti,Maria Lucia Angelotti,Alexa Burger,Paola Romagnani

doi:10.1038/s41467-018-03753-4

Abstract

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.

Highlights

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
Since Blood urea nitrogen (BUN) was too insensitive to detect the decline of kidney function, we directly measured glomerular filtration rate (GFR)
In this study, we questioned the current paradigm that functional recovery after AKI relates to a regenerative capacity of all TECs5,6

Summary

Introduction

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. Renal functional recovery upon AKI involves remnant tubular cell hypertrophy via endocycle and limited progenitordriven regeneration that can be pharmacologically enhanced. The current pathophysiological concept involves the assumption that every tubular epithelial cell (TEC) surviving the injury phase has the potential to dedifferentiate and proliferate to replace lost cells or even reepithelialize denuded tubule segments[5,6]. This concept has been evidenced by immunolabelling for cell cycle markers, such as Ki67, proliferating cell nuclear antigen (PCNA) or 5-bromo-2′deoxyuridine (BrdU) uptake[7]. We set three hypotheses: (1) the overall capacity of tubular regeneration after injury is largely overestimated; (2) cell cycle markers may not consistently represent cell division; (3) regeneration is limited to tubular progenitors and other TECs entering the cell cycle after AKI undergo endocycle-related hypertrophy

Methods

Results

Conclusion