Kidney injury molecule-1 (KIM-1) is the most up regulated 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, and generated monoclonal and polyclonal antibodies to, the human, mouse, pig, dog, zebrafish and rat KIM-1. The KIM-1 ectodomain is cleaved and found in the urine of patients with acute kidney injury or renal cell carcinoma and is a sensitive and specific biomarker for kidney 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. A mutant mouse lacking an extracellular domain that is important for phagocytosis and a transgenic mouse with Kim-1 expression in the renal tubule have important phenotypes supporting a critical role for this protein in acute and chronic kidney disease. The goal of this proposal is to further characterize the functional role of KIM-1 during acute and chronic injury to the kidney. We hypothesize that KIM-1 reduces the early inflammatory response to ischemic injury as it mediates uptake of apoptotic and necrotic debris from the damaged proximal tubule.
In Specific Aim 1 we will characterize and evaluate the phagocytic function of KIM-1 in protection of the kidney exposed to ischemia or toxins. A mutant mouse that is defective in phagocytosis sustains increased injury to the kidney in response to ischemia or cisplatin. The effects of Kim-1 on autophagy, inflammation and the innate immune response will be explored. The contributions of various extracellular and intracellular domains of KIM-1 on phagocytosis and autophagy will be evaluated. In our second specific aim we will explore our hypothesis that KIM-1's interactions with calreticulin on the cell surface of apoptotic and necrotic cell modulate the immunogenicity of cell death associated with acute kidney injury. A considerable number of patients with chronic kidney disease have elevated levels of KIM-1 protein in their urine and kidney tissue. In the third Specific Aim we will analyze the role of persistent KIM-1 expression on inflammation and chronic fibrosis. We have created a transgenic mouse which expresses low levels of Kim-1 in the kidney tubule. This mouse develops severe tubulointerstitial inflammatory disease, anemia, and cardiac hypertrophy and dies at 4-6 months of age with chronic renal failure. This is a novel model of chronic kidney disease and we hypothesize that chronic KIM-1 expression is maladaptive. We will explore the molecular processes responsible for this impressive kidney disease phenotype including the role of chronic KIM-1 expression in cell cycle arrest. In summary understanding the function of KIM-1 will provide important insight into the role of this protein in injury and repair processes of the kidney, and may identify KIM-1 as an important therapeutic target not only for acute and chronic renal disease but also for malignant transformation of the epithelial cell.

Public Health Relevance

Our goal is to understand how the kidney is able to repair itself after sustaining damage due to temporary reductions in blood flow or exposures to drugs which may injure the kidney. This work also is directed at learning how abnormal repair in the kidney can lead to progressive disease resulting in kidney failure. The work hopefully will lead to new understandings that can be used to develop new therapeutic drugs that can enhance recovery of the kidney when it is injured and prevent progression of kidney disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK072381-08
Application #
8298503
Study Section
Pathobiology of Kidney Disease Study Section (PBKD)
Program Officer
Hoshizaki, Deborah K
Project Start
2005-06-01
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
8
Fiscal Year
2012
Total Cost
$407,580
Indirect Cost
$162,982
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Wang, Xinhui; Bonventre, Joseph V; Parrish, Alan R (2014) The aging kidney: increased susceptibility to nephrotoxicity. Int J Mol Sci 15:15358-76
Zhang, Ping L; Mashni, Joseph W; Sabbisetti, Venkata S et al. (2014) Urine kidney injury molecule-1: a potential non-invasive biomarker for patients with renal cell carcinoma. Int Urol Nephrol 46:379-88
Bonventre, Joseph V (2014) Maladaptive proximal tubule repair: cell cycle arrest. Nephron Clin Pract 127:61-4
Bonventre, Joseph V (2014) Kidney injury molecule-1: a translational journey. Trans Am Clin Climatol Assoc 125:293-9; discussion 299
Sabbisetti, Venkata S; Waikar, Sushrut S; Antoine, Daniel J et al. (2014) Blood kidney injury molecule-1 is a biomarker of acute and chronic kidney injury and predicts progression to ESRD in type I diabetes. J Am Soc Nephrol 25:2177-86
Niewczas, Monika A; Sirich, Tammy L; Mathew, Anna V et al. (2014) Uremic solutes and risk of end-stage renal disease in type 2 diabetes: metabolomic study. Kidney Int 85:1214-24
Freedman, Benjamin S; Lam, Albert Q; Sundsbak, Jamie L et al. (2013) Reduced ciliary polycystin-2 in induced pluripotent stem cells from polycystic kidney disease patients with PKD1 mutations. J Am Soc Nephrol 24:1571-86
Nishihara, Kumiko; Masuda, Satohiro; Shinke, Haruka et al. (2013) Urinary chemokine (C-C motif) ligand 2 (monocyte chemotactic protein-1) as a tubular injury marker for early detection of cisplatin-induced nephrotoxicity. Biochem Pharmacol 85:570-82
Sabbisetti, Venkata S; Ito, Kazumi; Wang, Chang et al. (2013) Novel assays for detection of urinary KIM-1 in mouse models of kidney injury. Toxicol Sci 131:13-25
Humphreys, Benjamin D; Xu, Fengfeng; Sabbisetti, Venkata et al. (2013) Chronic epithelial kidney injury molecule-1 expression causes murine kidney fibrosis. J Clin Invest 123:4023-35

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