Ischemic Kidney Injury and Kidney Repair: Stress Granules

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AKI is a major kidney disease that is associated with high mortality, morbidity, and increasing prevalence. Moreover, incomplete or maladaptive kidney repair following AKI leads to chronic renal pathologies, contributing to CKD. Aging population, mirrored by veterans, is highly susceptible to both AKI and CKD. A key pathological feature of AKI is the damage of renal tubules and, accordingly, the past research has focused on tubular cell injury and death. However, it is known that, in response to injury, cells may activate intrinsic mechanisms or stress responses for self-protection and survival, and the cells die only when these mechanisms are overwhelmed or altered by severe or prolonged insult. Stress granule (SG) is a newly discovered, cytoplasmic structure formed in eukaryotic cells upon cell stress, which mainly contains RNAs and RNA-binding proteins. We recently demonstrated the first evidence of SG formation in stressed kidney tubular cells. We have now established the first mouse model in which the core SG gene G3BP1 is specifically ablated from kidney proximal tubule cells. In addition, we have identified CSDE1 as a novel binding protein of G3BP1. The goal of this application is to determine the pathologic role of SG in ischemic AKI and maladaptive kidney repair, and elucidate the molecular interaction between G3BP1 and CSDE1. We hypothesize that: Stress granules are induced in ischemic AKI to protect kidney tubular cells, but persistent stress granules after AKI may contribute to maladaptive repair. Through the interaction with G3BP1, CSDE1 plays an important role in SG formation during cell stress in conditions like ischemic AKI. We propose three specific aims to: (1) test the hypothesis that stress granules are induced in ischemic AKI to protect against renal tubular damage; (2) test the hypothesis that stress granules contribute to maladaptive kidney repair after ischemic AKI; and (3) test the hypothesis that CSDE1 plays an important role in stress granule formation through the interaction with G3BP1. This application will unveil the role of stress granules in AKI and post-AKI kidney repair, and elucidate G3BP1/CSDE1 interaction in stress granule formation. As such, completion of the work will not only gain significant insights into the regulation of stress granules, but may also identify stress granule as a novel therapeutic target for AKI and associated CKD, opening a new field of study.