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
Khan, Nayaab S; Song, Chi Young; Thirunavukkarasu, Shyamala et al. (2016) Cytosolic Phospholipase A2α Is Essential for Renal Dysfunction and End-Organ Damage Associated With Angiotensin II-Induced Hypertension. Am J Hypertens 29:258-65
Fischer, Krisztina; Meral, F Can; Zhang, Yongzhi et al. (2016) High-resolution renal perfusion mapping using contrast-enhanced ultrasonography in ischemia-reperfusion injury monitors changes in renal microperfusion. Kidney Int 89:1388-98
Yin, Wenqing; Naini, Said Movahedi; Chen, Guochun et al. (2016) Mammalian Target of Rapamycin Mediates Kidney Injury Molecule 1-Dependent Tubule Injury in a Surrogate Model. J Am Soc Nephrol 27:1943-57
Zuk, Anna; Bonventre, Joseph V (2016) Acute Kidney Injury. Annu Rev Med 67:293-307
Nowak, Natalia; Skupien, Jan; Niewczas, Monika A et al. (2016) Increased plasma kidney injury molecule-1 suggests early progressive renal decline in non-proteinuric patients with type 1 diabetes. Kidney Int 89:459-67
Waikar, Sushrut S; Sabbisetti, Venkata; Ärnlöv, Johan et al. (2016) Relationship of proximal tubular injury to chronic kidney disease as assessed by urinary kidney injury molecule-1 in five cohort studies. Nephrol Dial Transplant 31:1460-70
Basile, David P; Bonventre, Joseph V; Mehta, Ravindra et al. (2016) Progression after AKI: Understanding Maladaptive Repair Processes to Predict and Identify Therapeutic Treatments. J Am Soc Nephrol 27:687-97
Deml, Karl-Friedrich; Schildhaus, Hans-Ulrich; Compérat, Eva et al. (2015) Clear cell papillary renal cell carcinoma and renal angiomyoadenomatous tumor: two variants of a morphologic, immunohistochemical, and genetic distinct entity of renal cell carcinoma. Am J Surg Pathol 39:889-901
Ferenbach, David A; Bonventre, Joseph V (2015) Mechanisms of maladaptive repair after AKI leading to accelerated kidney ageing and CKD. Nat Rev Nephrol 11:264-76
Besschetnova, Tatiana Y; Ichimura, Takaharu; Katebi, Negin et al. (2015) Regulatory mechanisms of anthrax toxin receptor 1-dependent vascular and connective tissue homeostasis. Matrix Biol 42:56-73

Showing the most recent 10 out of 130 publications