Validation of recombinant truncated Tamm-Horsfall protein as a therapeutic tool for kidney injury

Acute kidney injury (AKI) is a major determinant of mortality and morbidity in hospitalized veterans. Unfortunately, AKI remains without a specific therapy. Tamm-Horsfall protein (THP) is expressed exclusively in the kidney by cells of the thick ascending limbs (TAL) of Henle. We previously showed that AKI induces a state of THP deficiency, and that THP is specifically targeted towards the interstitium of the kidney during recovery from injury. We established that the presence of THP is needed to terminate inflammatory signaling in the epithelium and promote healing through altering the phenotype of immune cells such as macrophages. Furthermore, chronic kidney disease (CKD), which is characterized by chronic THP deficiency, is a high-risk state for AKI. Therefore, developing a therapeutic strategy to exogenously supplement THP in veterans with states of THP deficiency will likely be very beneficial in improving the course of kidney injury and provide direly needed treatment and mitigation strategies against AKI The central hypothesis is that recombinant truncated THP has a favorable pharmacological profile that can be used efficaciously to improve the course of AKI, particularly in the setting of pre-existing deficiency. This hypothesis has been formulated on the basis of strong preliminary and published data. The following specific aims will be used to investigate this hypothesis. Aim 1 will establish the pharmacokinetics and safety of systemic recombinant truncated THP in control and murine models of AKI Aim 2 will demonstrate the efficacy of recombinant THP administration in various models of murine AKI (ischemia/reperfusion, cisplatin and LPS) using wild type and THP+/- mice. This research will involve the use recombinant THP produced in Chinese Hamster Ovary cells and various models of murine AKI. Outcomes of kidney injury severity measured through biochemical measures (filtration / injury markers), histological scoring, and assessing the burden of inflammatory cells. A long-term outcome of fibrosis (measured histologically at 4 weeks) will also be included. THP knockout, wild type and heterozygous mice will be used. This research will provide key validation strategies to advance the use of exogenously administered THP in AKI towards IND-enabling studies. The use of various models of AKI will ensure that the efficacy of recombinant THP has a broad scope and is not model dependent, which will further de-risk this therapeutic intervention.