Pericytes can undergo a phenotype switch similar to EMT and acquire myofibroblast characteristics upon injury115. We will then discuss how the repair mechanism of tubular cells becomes maladaptive, and we will finally discuss the intercellular crosstalk in the interstitium that ultimately proceeds tubulointerstitial fibrosis. Facts TECs are vulnerable to injury in a variety of CKDs. TECs are actually participants, rather than victims or bystanders, in the progression of renal fibrosis.Please check your article carefully, coordinate with any co-authors and enter all final edits clearly in the eproof, remembering to save frequently. Once corrections are submitted, we cannot routinely make further changes to the article.Article checked TECs can start repair mechanisms upon injury, though these mechanisms sometimes aggravate renal fibrosis. TECs interact with other cell types in the interstitium, leading to renal fibrosis. Note that the eproof should be amended in only one browser window at any one time; otherwise changes will be overwritten.Understood, thanks for reminding. Open questions Are TECs profibrotic or antifibrotic in MBX-2982 the progression of tubulointerstitial fibrosis?Author surnames have been highlighted. Please check these carefully and adjust if the first name or surname is marked up incorrectly. Note that changes here will affect indexing of your article in public repositories such as PubMed. Also, carefully check the spelling and numbering of all author names and affiliations, and the corresponding email address(es).Authors’ names have been checked. They are correct. How do TECs change the microenvironment in the interstitium upon injury? Where is the borderline between beneficial repair and maladaptive repair for TECs upon injury? Are cell senescence and epithelialCmesenchymal transition different facets of the same process? Is it possible to target TECs to alleviate CKDs in clinical settings in the future? Introduction Chronic kidney diseases (CKDs) have exerted a great burden on public health worldwide. According to the WHO estimate, CKD accounted for 1.5% of deaths worldwide in 20121. Renal fibrosis, especially tubulointerstitial fibrosis (TIF), is the inevitable outcome of all progressive CKD2, and therefore, exploring the intrinsic mechanisms of TIF is of great importance. TIF is manifested by tubular atrophy and the accumulation of extracellular matrix (ECM)3. For a long time, interests have focused on fibroblasts and myofibroblasts. However, in recent years, a growing number of studies are shedding light on the role of tubular epithelial cells (TECs) in renal fibrosis4. Evidence has shown that TECs, rather than being victims OPD1 or bystanders, are probably an initiator of the TIF response to a variety of injuries5. The maladaptive repair mechanisms of TECs can be the key point of progression from acute to chronic disease6. In this review, we will focus on the role of TECs as an important mediator of TIF upon injury.Please note that after the paper has been formally accepted you can only provide amended Supplementary Information files for critical changes to the scientific content, not for style. You should clearly explain what changes have been made if you do resupply any such files.Understood. Thanks for reminding.Should you wish to order offprints, please click on www.nature.com/aj/forms/bmt_offprint_2017.pdf to download and complete the offprint form and upload the completed form along with the article.Understood. Thanks for reminding. What are the intracellular changes of TECs upon injury? Mitochondria dysfunction and reactive oxygen species (ROS) aggravate tubular injury Mitochondrial impairment may aggravate TEC injury by disturbing energy metabolism and activating ROS and NLR family pyrin domain containing 3 (NLRP3)/inflammasomes (Fig.?1). A genome-wide transcriptome study on kidney biopsy specimens with TIF showed the deposition of lipid in TECs along with decreased expression of enzymes related to fatty MBX-2982 acid oxidation (FAO)7. Inhibition of FAO leads to a fibrotic phenotype change in TECs, while restoring FAO attenuates TIF7. The impairment of FAO is attributed to the downregulation of peroxisome proliferator-activated receptor ? and overexpression of miR-218C10. The loss of FAO also drives a metabolic switch to glycolysis in TECs to meet energy demands11. Impaired mitochondrial function also leads to the production of ROS and oxidative stress in TECs8, 12. Studies on diabetic nephropathy (DN) show that the accumulation of advanced oxidation protein products (AOPPs) results in mitochondrial injury and oxidative stress12. Production of ROS in the mitochondria can further lead to the activation of NLRP313C15. Two earlier studies showed increased mitochondrial ROS production along with NLRP3/inflammasome activation. Inhibition of mitochondrial ROS production simultaneously inhibits the activation of NLRP3 and downstream interleukin-1 (IL-1) and IL-18 production, indicating the presence of mitochondrial ROS prior to the MBX-2982 activation of NLRP313, 14,. A recent study showed that this process is probably mediated by the mROSCTXNIPCNLRP3 pathway15. Mitochondrial ROS can also increase the expression of several other proinflammatory.