Cells face constant microenvironmental changes that require them to adapt. If these fluctuations are beyond a certain threshold, cells become stressed and their viability will be challenged [1]. The kidney integrates a considerable number of stresses that challenge tissue viability and organization, which may result in interstitial fibrosis, tubular atrophy and chronic kidney disease [2, 3]. These stresses can be toxic, ischaemic, immunologic, infectious, haemodynamic or metabolic. When challenged by injuries, kidney cells engage evolutionary adaptive programs that regulate cellular metabolism in response to microenvironmental fluctuations. Critical biological programs include mammalian target of rapamycin (mTOR) signalling, hypoxia inducible factor (HIF)-1α activation, the unfolded protein response (UPR) or macroautophagy. The cell fate will depend on the integration of the type and intensity of cellular stresses as well as the imbalance of pro-survival and pro-death pathways. Beyond metabolic adaptation and cell survival regulation, biological adaptive programs modulate other cellular functions, including immunity [4, 5].

Following injury, kidney epithelial cells undergo phenotypic changes that are usually characterized by the loss of epithelial markers and the expression of mesenchymal markers [6]. Whether these changes correspond to a complete epithelial-to-mesenchymal transition (EMT), which occurs during oncogenesis, is the subject of considerable controversy [7]. However, it is assumed that in vivo in the kidney, the EMT is not complete, which excludes the migratory properties of epithelial cells [8] and it contributes to pathological changes, including tubular atrophy and interstitial fibrosis [9, 10].

Master regulators of EMT include extrinsic signals such as transforming growth factor-β or WNT signalling [11] and intrinsic signals such as HIF-1α-mediated responses to hypoxia [12]. The distinction between extrinsic …

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