The proximal tubule responds to chronic injury with adaptive and maladaptive outcome. Normally, proximal tubule cells are quiescent with low rates of entry in the cell cycle (G₀). When injured, proximal tubule cells enter the cell cycle at higher rates but fail to progress to mitosis. Damage to DNA and the endoplasmic reticulum provokes cyclin kinase inhibitors (CKIs) to block proximal tubule cells at several stages of the cell cycle (10). Injured proximal tubule cells dedifferentiate as they lose their brush border, have decreased E-cadherin expression and increased vimentin expression, and lose transport proteins. These dedifferentiated cells are the source of many genes underpinning repair or activating neighboring cells, including the immediate early genes, such as the mitogen activated kinases that could either aide or impair repair. Yen-Ting Chen et al. showed that fibroblasts from fibrotic mouse kidneys upregulated TXNDC5, which was controlled by the ATF6-dependent ER stress pathway (1). Chronic injury alters the proximal tubule cell metabolism by inhibiting mitochondrial fatty acid oxidation, generating superoxide, increasing potentially damaging triglycerides, and provoking ferroptotic cell death. Injured proximal tubule cells also undergo the unfolded protein response and autophagy, which arrests the cell cycle and promotes senescence. Each injured compartment may provoke secretion of inflammatory mediators that may attract or activate particular cells to amplify or repair the injury. The balance between adaptive and maladaptive pathways depends on the particular insult as well as its duration and severity.