Kidney Injury Molecule-1 in Epithelial Repair

Project Summary/ Abstract
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, and created monoclonal
and polyclonal antibodies to, human, mouse, rat, pig, dog, and zebrafish KIM-1. We have reported that the
KIM-1 ectodomain is cleaved into the blood and urine of subjects with acute (AKI) and chronic (CKD) kidney
injury and is a sensitive and specific kidney injury biomarker to detect kidney injury and predict progression of
CKD. KIM-1 has been qualified by the FDA for preclinical and clinical use in kidney 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 phagocytosis pathway that links
autophagy to KIM-1-mediated phagosome maturation and MHC restricted antigen presentation in epithelial
cells. We have shown that KIM-1 expression in early AKI is adaptive, but chronic expression leads to
CKD with severe fibrosis, secondary hypertension, and cardiac hypertrophy. A mouse lacking the
extracellular mucin domain, important for phagocytosis, is protected against development of fibrosis. We
have found that KIM-1 mediates uptake of palmitate-bound albumin and recently found an inhibitor of KIM-1-
mediated phagocytosis by screening a small molecule library. The inhibitor reduces cell lipotoxicity and
fibrosis in a novel mouse model of diabetic kidney disease. The current competing renewal application builds
upon and extends our prior findings. Our goal is to further characterize KIM-1-mediated uptake of fatty acid
bound albumin (FA-Albumin), and the implications of this uptake for cellular injury and maladaptive repair,
including cell senescence leading to profibrotic and proinflammatory responses that ultimately lead to
progressive CKD. KIM-1 may be a drug target to prevent and treat CKD. We hypothesize that persistent
KIM-1-mediated endocytosis of FA-Albumin and subsequent signaling leads to toxicity. FA-Albumin
uptake leads to a mitochondrial dysfunction, DNA damage response (DDR), G2/M arrest, mTOR
signaling, TASCC formation, and a prosecretory fibrotic phenotype. In addition KIM-1-FA-Albumin
uptake leads to chronic tissue inflammation in part due to tertiary
lymphoid tissue development through LTaβ/LTβR signaling. In Specific Aim 1 we will characterize
binding of KIM-1 to FA-Albumin and determine the architecture, structural dynamics and molecular basis for
FA-Albumin binding to KIM-1. In Specific Aim 2 we will characterize the intracellular consequences of KIM-1
mediated FA-Albumin endocytosis, particularly on mitochondrial function, DNA damage, the DDR, cell cycle
arrest and the profibrotic secretome. In Specific Aim 3 we will evaluate the role of KIM-1 mediated FA-
Albumin uptake and DDR in LTaβ/LTβR signaling leading to tertiary lymphoid tissue (TLT) formation
with consequent pro-inflammatory consequences in animal models of AKI to CKD transition.

Grant Number: 5R01DK072381-19
NIH Institute/Center: NIH
Principal Investigator: JOSEPH BONVENTRE