Kidney injury molecule-1 (KIM-1) is the most upregulated protein in proximal tubular epithelial cells in various states characterized by epithelial cell dedifferentiation: ischemia, toxic renal injury, and renal cell carcinoma. We have cloned, generated cells and animals expressing wild-type and mutant KIM-1, as well as monoclonal and polyclonal antibodies to human, mouse, rat, pig, dog, and zebrafish KIM-1. The KIM-1 ectodomain is cleaved and found in the urine of patients with acute kidney injury (AKI) and chronic kidney disease (CKD), serving as a sensitive and specific kidney injury biomarker of injury, qualified by the FDA for preclinical safety studies, and currently used in many clinical safety studies. We have discovered that KIM-1 transforms kidney epithelial cells into semiprofessional phagocytes making it the first nonmyeloid phosphatidylserine receptor. We have described a novel KIM-1-mediated phagocytosis pathway by which autophagy regulates phagocytosis and MHC-restricted antigen presentation in epithelial cells. While KIM-1 expression in AKI is adaptive, a transgenic mouse which expresses KIM-1 in the renal tubule develops CKD with severe fibrosis, secondary hypertension, and cardiac hypertrophy. A mutant mouse lacking the extracellular mucin domain, important for phagocytosis, is protected against development of fibrosis. We have found that KIM-1 internalizes albumin-bound fatty acids and oxidized lipoproteins which induce a DNA-repair response (DDR) and trigger profibrotic factor production. We have demonstrated that the DDR leading to G2/M cell cycle arrest is an important contributor to a senescence?associated profibrotic secretory phenotype. The goal of this proposal is to further characterize the functional role of KIM-1 during chronic kidney injury. We hypothesize that persistent KIM-1 signaling activates a proliferative response as well as a DDR leading to G2/M arrest and a prosecretory fibrotic phenotype. KIM-1-ligand interactions lead to altered cell-matrix interactions leading to enhanced TGF? activation. Finally with persistent KIM-1 expression a state of autophagy insufficiency is generated resulting in GATA activation and an additional non-DDR dependent fibrotic response.
In Specific Aim 1 we will evaluate whether KIM-1-induced mTOR activation leads to dedifferentiation and proliferation which, together with G2/M arrest due to the DDR, results in a profibrotic secretory phenotype.
In Specific Aim 2 we will evaluate whether the upregulation of ECM components by KIM-1 expression promotes activation of TGF? and YAP-induced entry into the cell cycle which, in the setting of the DDR, potentiates kidney fibrosis.
In Specific Aim 3 we will determine whether an impaired autophagic response associated with uptake of endocytic ligands by KIM-1 triggers the activation of GATA4, DNA damage, senescence and G2/M arrest. There are therapeutic implications for our studies since agents that interfere with mTOR, fibronectin, or the HIPPO-YAP pathway or stimulate autophagy, are in development and our studies will hopefully motivate KIM-1-directed therapeutics to prevent or mitigate progression of CKD.
We have discovered a protein, Kidney Injury Molecule-1 (KIM-1), that proximal tubule kidney cells express when they are injured. If KIM-1 is expressed over longer periods of time it leads to progressive kidney failure. Our goal is to understand how the protein leads to organ failure so that we can develop strategies to interrupt its effect and prevent progression of chronic kidney disease, reducing side effects such as cardiovascular disease and the need for hemodialysis or transplantation.
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