This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Acute ischemic kidney injury following cardiovascular disease, sepsis and shock causes significant morbidity and mortality. Notably, this damage can be repaired through endogenous mechanisms, and these regenerative pathways present tractable therapeutic targets. In animal models of acute ischemic kidney injury, bone morphogenetic proteins (BMPs) are protective. We now show that robust expression of multiple BMPs is maintained following renal injury, and postulate that interventive modulation of BMP signals may comprise a potent therapeutic strategy. Specifically, we propose to assess renoprotective effects of modulating levels of extracellular BMP regulators in the diseased kidney, and have identified two novel candidates of outstanding interest. Chordin-like 1 expression is strongly downregulated following acute kidney injury, indicating that its regulation may be a feature of the kidney's regenerative response. Conversely, follistatin-like 1 expression is sustained after injury, indicating that it may antagonize the renoprotective effects of BMPs, and delay regenerative responses. To define relationships between BMP signaling, BMP antagonism and tissue regeneration in the injured kidney, we propose: i) To evaluate the role of chordin-like 1 regulation on renoprotection and regenerative responses to injury, and ii) To investigate renoprotective and pro-regenerative effects of inactivating follistatin-like 1. The overall significance of this project lies in defining the roles of two novel BMP modulating proteins in kidney regeneration, and the associated identification of potential therapeutic targets for kidney disease.
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