Renal diseases can be progressively complicated by Chronic kidney diseases (CKD), whatever the initial renal injury. CKD represent a worldwide health concern: about 10%-15% of the overall population is affected by CKD worldwide and this number is expected to increase. CKD has also dramatic consequences in patient’ morbidity and mortality, including cardiovascular morbidity. Glomerular injuries are a major cause of CKD (leading to 30% incident dialysis cases each year in France). Among glomerular injuries, the most severe forms are glomerulonephritis with extracapillary proliferation, leading to nephron loss and end stage renal diseases in few weeks. Similar histological lesions are also observed in collapsing forms of focal segmental glomerulosclerosis. The implication of several cellular stress pathways in glomerular epithlial cells during kidney disease progression has been recently suggested. Interestingly, we have identified a specific molecular signature of cellular stress (heat shock protein 27 induction) during several glomerular diseases, both in human and mouse models. HSP27 induction is mainly detected in glomerular parietal epithelial cells (PEC), whihch have recently been crucially implicated in glomerular diseases pathophysiology. Moreover, we have shown that inhibition of this pathway was associated with improvement of glomerular lesions in mouse models, and inhibition of PEC activation and migration in vitro. In the current project, by combining in vivo models of genetically modified mice, pharmacological approaches and in vitro studies of cultured glomerular PEC, we will attempt to identify the role of HSP27 in glomerular PEC after renal injury. Cellular mechanisms such as proliferation, migration or activation/dedifferentiation will be studied. In a candidate approach, we will analyze specific signalling pathways which could be involved in glomerular diseases pathophysiology and modulated by HSP27. Unbiaised global approaches using transciptomic and proteomic strategies will be also studied in HSP27- depleted PEC, according to the first results. Moreover, this signature will be studied in human available samples (blood or urine) to evaluate its potential role of non-invasive biomarker in predicting disease activity and progression. To this aim, new and highly specific tools (aptamers, exosomes extraction and characterization) will be developed and tested, according to procedures already mastered by the collaborators of the project. By identifying the exact role of HSP27 in glomerular diseases pathophysiology, this study could lead to new therapeutic strategies in human kidney diseases, since this pathway could be targeted with inhibitors already available in clinics. Besides, this work could allow us to propose new diagnostic strategies using this signature as a disease activity biomarker. Therefore, our project has the potential to develop a personalized medicine strategy in a wide range of glomerular diseases. Lastly, this study will have crucial pathophysiological implications. Given the essential role of heat shock signature during several cellular stresses (such as metabolic, hypoxic, oxidative stress), this work opens new research field in stress pathways implicated during glomerular diseases. This proposal will benefit of the complementarities between clinicians implicated in clinical research and both basic science and physiopathological model experts. By understanding the role of HSP27 in glomerular diseases, this project should have a crucial impact in strategies inhibiting glomerular disease evolution.