Abstract BACKGROUND AND AIMS Acute Kidney Injury (AKI) is characterized by a rapid deterioration of kidney function. Recently, we showed that tubular epithelial cells (TC) respond to AKI by triggering polyploidy, a condition in which a normally diploid cell acquires additional sets of chromosomes. Polyploidy offers several advantages, but in the kidney the biological significance of polyploidization remains unclear. In this study we hypothesized that polyploidy (i) is the predominant cellular response early during AKI and (ii) that is an adaptive stress response required to maintain a residual kidney function assuring survival. METHOD To address these hypotheses, we employed in vivo transgenic models based on the Fluorescence Ubiquitin Cell Cycle Indicator (FUCCI) technology in combination with YAP1 downregulation. In these models, mice were subjected to unilateral ischemia reperfusion injury (IRI) or glycerol-induced rhabdomyolysis to induce AKI. Polyploid cells have been then characterized by single cell-RNA sequencing analysis, cell sorting, FACS analysis, super-resolution and transmission electron microscopy. RESULTS After AKI, YAP1 is activated triggering TC polyploidization. Polyploid TC increase in parallel to massive cell death triggered by AKI suggesting that polyploidization could be a means to escape cell death. Indeed, we found that polyploid TC tends to accumulate genome instability and survive, while diploid TC do not. Of note, virtually all dying cells were cycling cells based on the Fucci2aR reporter suggesting that TC death occurred during the S or G2/M phase. As polyploid TC increase immediately following AKI, they may be required to survive injury and damage by sustaining renal function. In order to evaluate the functional role of polyploid cells during AKI, we generated mice where YAP1 is knocked-out specifically in TC (YAP1ko mice). Indeed, after AKI, YAP1ko mice showed a reduced number of polyploid cells, worsened kidney function and a dramatic reduction of mouse survival, proving that polyploidization is required to survive AKI. CONCLUSION We demonstrated that (i) after AKI TC accumulate genome instability and die or become polyploidy; (ii) TC polyploidy is essential to preserve residual kidney function immediately after AKI.