KIDNEY INJURY MOLECULE-1 IN EPITHELIAL REPAIR

Summary

Principal Investigator: JOSEPH VINCENT BONVENTRE
Abstract: DESCRIPTION (provided by applicant): 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.
Funding Period: 2005-06-01 - 2015-05-31
more information: NIH RePORT

Top Publications

  1. pmc Uremic solutes and risk of end-stage renal disease in type 2 diabetes: metabolomic study
    Monika A Niewczas
    1 Section on Genetics and Epidemiology, Research Division, Joslin Diabetes Center, Boston, Massachussetts, USA 2 Department of Medicine, Harvard Medical School, Boston, Massachussetts, USA
    Kidney Int 85:1214-24. 2014
  2. pmc Targeted proximal tubule injury triggers interstitial fibrosis and glomerulosclerosis
    Ivica Grgic
    Renal Division, Department of Medicine, Brigham and Women s Hospital, Harvard Medical School, Boston, MA 02115, USA
    Kidney Int 82:172-83. 2012
  3. pmc Imaging of podocyte foot processes by fluorescence microscopy
    Ivica Grgic
    Renal Division, Department of Medicine, Brigham and Women s Hospital, Harvard Institutes of Medicine, Boston, MA 02115, USA
    J Am Soc Nephrol 23:785-91. 2012
  4. pmc Structural equation modeling highlights the potential of Kim-1 as a biomarker for chronic kidney disease
    Lesley Gardiner
    College of Medicine, Texas A and M Health Science Center, Bryan, TX, USA
    Am J Nephrol 35:152-63. 2012
  5. pmc Loss of leucine-rich repeat kinase 2 causes age-dependent bi-phasic alterations of the autophagy pathway
    Youren Tong
    Center for Neurologic Diseases, Department of Neurology, Brigham and Women s Hospital, Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA
    Mol Neurodegener 7:2. 2012
  6. pmc Cellular pathophysiology of ischemic acute kidney injury
    Joseph V Bonventre
    Renal Division, Brigham and Women s Hospital, Boston, Massachusetts, USA
    J Clin Invest 121:4210-21. 2011
  7. ncbi Pathophysiology of acute kidney injury to chronic kidney disease: maladaptive repair
    Li Yang
    Renal Division, Brigham and Women s Hospital, Harvard Medical School, Boston, MA, USA
    Contrib Nephrol 174:149-55. 2011
  8. pmc Repair of injured proximal tubule does not involve specialized progenitors
    Benjamin D Humphreys
    Renal Division, Brigham and Women s Hospital, Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
    Proc Natl Acad Sci U S A 108:9226-31. 2011
  9. pmc Immunohistochemical distinction of primary adrenal cortical lesions from metastatic clear cell renal cell carcinoma: a study of 248 cases
    Ankur R Sangoi
    Department of Pathology, El Camino Hospital, Mountain View, Palo Alto, CA, USA
    Am J Surg Pathol 35:678-86. 2011
  10. pmc Regression of microalbuminuria in type 1 diabetes is associated with lower levels of urinary tubular injury biomarkers, kidney injury molecule-1, and N-acetyl-β-D-glucosaminidase
    Vishal S Vaidya
    Renal Division, Department of Medicine, Brigham and Women s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
    Kidney Int 79:464-70. 2011

Detail Information

Publications61

  1. pmc Uremic solutes and risk of end-stage renal disease in type 2 diabetes: metabolomic study
    Monika A Niewczas
    1 Section on Genetics and Epidemiology, Research Division, Joslin Diabetes Center, Boston, Massachussetts, USA 2 Department of Medicine, Harvard Medical School, Boston, Massachussetts, USA
    Kidney Int 85:1214-24. 2014
    ..Thus, abnormal plasma concentrations of putative uremic solutes and essential amino acids either contribute to progression to ESRD or are a manifestation of an early stage(s) of the disease process that leads to ESRD in T2D. ..
  2. pmc Targeted proximal tubule injury triggers interstitial fibrosis and glomerulosclerosis
    Ivica Grgic
    Renal Division, Department of Medicine, Brigham and Women s Hospital, Harvard Medical School, Boston, MA 02115, USA
    Kidney Int 82:172-83. 2012
    ..Thus, selective epithelial injury can drive the formation of interstitial fibrosis, capillary rarefaction, and potentially glomerulosclerosis, substantiating a direct role for damaged tubule epithelium in the pathogenesis of CKD...
  3. pmc Imaging of podocyte foot processes by fluorescence microscopy
    Ivica Grgic
    Renal Division, Department of Medicine, Brigham and Women s Hospital, Harvard Institutes of Medicine, Boston, MA 02115, USA
    J Am Soc Nephrol 23:785-91. 2012
    ..In summary, using this method of genetic labeling and conventional fluorescence microscopy to visualize podocyte foot processes will complement electron microscopy and facilitate the analysis of podocytes and their precursors in vivo...
  4. pmc Structural equation modeling highlights the potential of Kim-1 as a biomarker for chronic kidney disease
    Lesley Gardiner
    College of Medicine, Texas A and M Health Science Center, Bryan, TX, USA
    Am J Nephrol 35:152-63. 2012
    ..SEM's ability to investigate complex relationships in an efficient, single model could be utilized to understand the progression of CKD, as well as to develop a predictive model to assess kidney status in the patient...
  5. pmc Loss of leucine-rich repeat kinase 2 causes age-dependent bi-phasic alterations of the autophagy pathway
    Youren Tong
    Center for Neurologic Diseases, Department of Neurology, Brigham and Women s Hospital, Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA
    Mol Neurodegener 7:2. 2012
    ..We previously reported that loss of LRRK2 causes impairment of protein degradation pathways as well as increases of apoptotic cell death and inflammatory responses in the kidney of aged mice...
  6. pmc Cellular pathophysiology of ischemic acute kidney injury
    Joseph V Bonventre
    Renal Division, Brigham and Women s Hospital, Boston, Massachusetts, USA
    J Clin Invest 121:4210-21. 2011
    ....
  7. ncbi Pathophysiology of acute kidney injury to chronic kidney disease: maladaptive repair
    Li Yang
    Renal Division, Brigham and Women s Hospital, Harvard Medical School, Boston, MA, USA
    Contrib Nephrol 174:149-55. 2011
    ....
  8. pmc Repair of injured proximal tubule does not involve specialized progenitors
    Benjamin D Humphreys
    Renal Division, Brigham and Women s Hospital, Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
    Proc Natl Acad Sci U S A 108:9226-31. 2011
    ..Thus, nonlethally injured cells repopulate the kidney epithelium after injury in the absence of any specialized progenitor cell population...
  9. pmc Immunohistochemical distinction of primary adrenal cortical lesions from metastatic clear cell renal cell carcinoma: a study of 248 cases
    Ankur R Sangoi
    Department of Pathology, El Camino Hospital, Mountain View, Palo Alto, CA, USA
    Am J Surg Pathol 35:678-86. 2011
    ....
  10. pmc Regression of microalbuminuria in type 1 diabetes is associated with lower levels of urinary tubular injury biomarkers, kidney injury molecule-1, and N-acetyl-β-D-glucosaminidase
    Vishal S Vaidya
    Renal Division, Department of Medicine, Brigham and Women s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
    Kidney Int 79:464-70. 2011
    ..Hence, tubular dysfunction is a critical component of the early course of diabetic nephropathy...
  11. pmc TIM2 gene deletion results in susceptibility to cisplatin-induced kidney toxicity
    Aparna Krishnamoorthy
    Renal Division, Department of Medicine, Brigham and Women s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
    Toxicol Sci 118:298-306. 2010
    ....
  12. pmc Kidney injury molecule-1 outperforms traditional biomarkers of kidney injury in preclinical biomarker qualification studies
    Vishal S Vaidya
    Renal Division, Department of Medicine, Brigham and Women s Hospital, Harvard Medical School, Boston, Massachusetts, USA
    Nat Biotechnol 28:478-85. 2010
    ..This should enable early identification and elimination of compounds that are potentially nephrotoxic...
  13. pmc Epithelial cell cycle arrest in G2/M mediates kidney fibrosis after injury
    Li Yang
    Department of Medicine, Renal Division, Brigham and Women s Hospital, Harvard Medical School, Boston, Massachusetts, USA
    Nat Med 16:535-43, 1p following 143. 2010
    ..Hence, epithelial cell cycle arrest at G2/M and its subsequent downstream signaling are hitherto unrecognized therapeutic targets for the prevention of fibrosis and interruption of the accelerated progression of kidney disease...
  14. ncbi Pathophysiology of AKI: injury and normal and abnormal repair
    Joseph V Bonventre
    Renal Division, Brigham and Women s Hospital and Department of Medicine, Harvard Medical School, Boston, Mass 02115, USA
    Contrib Nephrol 165:9-17. 2010
    ..The epithelium plays an important role in abnormal repair through a recently defined link between cell cycle arrest of the epithelial cell and profibrogenic cytokine production...
  15. pmc Kim-1/Tim-1 and immune cells: shifting sands
    Takaharu Ichimura
    Renal Division, Department of Medicine, Brigham and Women s Hospital, Harvard Medical School, Boston, Massachusetts 02215, USA
    Kidney Int 81:809-11. 2012
    ....
  16. pmc Elevated urinary levels of kidney injury molecule-1 among Chinese factory workers exposed to trichloroethylene
    Roel Vermeulen
    Institute for Risk Assessment Sciences, Utrecht University, Utrecht, The Netherlands
    Carcinogenesis 33:1538-41. 2012
    ..The findings suggest that at relatively low occupational exposure levels a toxic effect on the kidneys can be observed. This finding supports the biological plausibility of linking TCE exposure and renal cancer...
  17. pmc Reduced ciliary polycystin-2 in induced pluripotent stem cells from polycystic kidney disease patients with PKD1 mutations
    Benjamin S Freedman
    Renal Division and Harvard Center for Polycystic Kidney Disease Research, Department of Medicine, Brigham and Women s Hospital, Harvard Medical School, Boston, Massachusetts
    J Am Soc Nephrol 24:1571-86. 2013
    ..Taken together, these results suggest that PC1 regulates ciliary PC2 protein expression levels and support the use of PKD iPS cells for investigating disease pathophysiology. ..
  18. pmc Urine kidney injury molecule-1: a potential non-invasive biomarker for patients with renal cell carcinoma
    Ping L Zhang
    Department of Anatomic Pathology, William Beaumont Hospital, 3601 W 13 Mile Rd, Royal Oak, MI, USA
    Int Urol Nephrol 46:379-88. 2014
    ..This study was designed to prospectively examine urine KIM-1 level before and 1 month after removal of renal tumors...
  19. pmc Chronic epithelial kidney injury molecule-1 expression causes murine kidney fibrosis
    Benjamin D Humphreys
    Renal Division, Brigham and Women s Hospital, Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA
    J Clin Invest 123:4023-35. 2013
    ..Thus, sustained KIM-1 expression promotes kidney fibrosis and provides a link between acute and recurrent injury with progressive chronic kidney disease...
  20. pmc Urinary chemokine (C-C motif) ligand 2 (monocyte chemotactic protein-1) as a tubular injury marker for early detection of cisplatin-induced nephrotoxicity
    Kumiko Nishihara
    Department of Pharmacy, Kyoto University Hospital, Faculty of Medicine, Sakyo ku, Kyoto 606 8507, Japan
    Biochem Pharmacol 85:570-82. 2013
    ....
  21. pmc Can we target tubular damage to prevent renal function decline in diabetes?
    Joseph V Bonventre
    Renal Division, Brigham and Women s Hospital, Department of Medicine, Harvard Medical School, Boston, MA, USA
    Semin Nephrol 32:452-62. 2012
    ..Local ischemia ensues with further injury to the tubules, more profibrogenic mediators, matrix protein deposition, fibrosis, and glomerulosclerosis...
  22. pmc High risk of ESRD in type 1 diabetes: new strategies are needed to retard progressive renal function decline
    Andrzej S Krolewski
    Research Division of the Joslin Diabetes Center, Harvard Medicial School, Boston, MA, USA
    Semin Nephrol 32:407-14. 2012
    ..Consistent with concepts of personalized medicine, the new interventions should be tailored to and evaluated in patients predicted to have rapid, moderate, or even slow progression to ESRD...
  23. pmc Novel assays for detection of urinary KIM-1 in mouse models of kidney injury
    Venkata S Sabbisetti
    Renal Division, Department of Medicine, Brigham and Women s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
    Toxicol Sci 131:13-25. 2013
    ..Mouse KIM-1 was stable for multiple freeze-thaw cycles, for up to 5 days at room temperature and up to at least an year when stored at -80°C...
  24. pmc Mechanism-based urinary biomarkers to identify the potential for aminoglycoside-induced nephrotoxicity in premature neonates: a proof-of-concept study
    Stephen J McWilliam
    MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdom
    PLoS ONE 7:e43809. 2012
    ..Further studies to investigate the clinical utility of novel urinary biomarkers in comparison to serum creatinine need to be undertaken...
  25. pmc Defect in regulatory B-cell function and development of systemic autoimmunity in T-cell Ig mucin 1 (Tim-1) mucin domain-mutant mice
    Sheng Xiao
    Center for Neurologic Disease, Brigham and Women s Hospital, Harvard Medical School, Boston, MA 02115, USA
    Proc Natl Acad Sci U S A 109:12105-10. 2012
    ..Thus, Tim-1 plays a critical role in maintaining suppressive Breg function, and our data also demonstrate an unexpected role of the Tim-1 mucin domain in regulating Breg function and maintaining self-tolerance...
  26. pmc Associations of urinary levels of kidney injury molecule 1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) with kidney function decline in the Multi-Ethnic Study of Atherosclerosis (MESA)
    Carmen A Peralta
    San Francisco VA Medical Center, San Francisco, CA 94121, USA
    Am J Kidney Dis 60:904-11. 2012
    ..Whether elevations in levels of urinary biomarkers of tubular injury (urine neutrophil gelatinase-associated lipocalin [NGAL] and kidney injury molecule 1 [KIM-1]) are associated with future risk of kidney disease has not been investigated...
  27. pmc Urinary liver-type fatty acid-binding protein predicts adverse outcomes in acute kidney injury
    Michael A Ferguson
    Division of Nephrology, Department of Medicine, Children s Hospital Boston, Harvard Medical School, Boston, Massachusetts 02115, USA
    Kidney Int 77:708-14. 2010
    ..Our study shows that age-adjusted urinary L-FABP levels were significantly higher in patients with poor outcome, defined as the requirement for renal replacement therapy or the composite end point of death or renal replacement therapy...
  28. pmc Comparative analysis of urinary biomarkers for early detection of acute kidney injury following cardiopulmonary bypass
    Orfeas Liangos
    Division of Nephrology, Caritas St Elizabeth s Medical Center, Boston, MA 02135, USA
    Biomarkers 14:423-31. 2009
    ..006). In this small pilot cohort, KIM-1 performed best as an early biomarker for AKI. Larger studies are needed to explore further the role of biomarkers for early detection of AKI following cardiac surgery...
  29. pmc Kidney injury molecule-1 is an early noninvasive indicator for donor brain death-induced injury prior to kidney transplantation
    W N Nijboer
    Surgery Research Laboratory and Department of Surgery, University Medical Center Groningen, University of Groningen, The Netherlands
    Am J Transplant 9:1752-9. 2009
    ..001) and 1 year (p < 0.05) after kidney transplantation. In conclusion, we think that Kim-1 is a promising novel marker for the early, organ specific and noninvasive detection of brain death-induced donor kidney damage...
  30. ncbi Shedding of the urinary biomarker kidney injury molecule-1 (KIM-1) is regulated by MAP kinases and juxtamembrane region
    Zhiwei Zhang
    Renal Division, Brigham and Women s Hospital, Department of Medicine, Harvard Medical School, and Harvard Massachusetts Institute of Technology Division of Health Sciences and Technology, Boston, Massachusetts, USA
    J Am Soc Nephrol 18:2704-14. 2007
    ..Mutagenesis studies demonstrated that the juxtamembrane secondary structure, not the primary amino acid sequence, was critical to the cleavage of KIM-1...
  31. ncbi Rapid screening of glomerular slit diaphragm integrity in larval zebrafish
    Dirk M Hentschel
    Renal Division, Department of Medicine, Brigham and Women s Hospital, HIM 550, 4 Blackfan Circle, Boston, MA 02115, USA
    Am J Physiol Renal Physiol 293:F1746-50. 2007
    ..These findings document the value of the zebrafish model in genomics and pharmacological screening applications...
  32. ncbi Can we rely on blood urea nitrogen as a biomarker to determine when to initiate dialysis?
    Sushrut S Waikar
    Clin J Am Soc Nephrol 1:903-4. 2006
  33. ncbi Pathophysiology of acute kidney injury: roles of potential inhibitors of inflammation
    Joseph V Bonventre
    Renal Division, Brigham and Women s Hospital and Department of Medicine, Harvard Stem Cell Institute, Harvard Medical School and Harvard Massachusetts Institute of Technology, Boston, MA 02115, USA
    Contrib Nephrol 156:39-46. 2007
    ..Understanding how these anti-inflammatory processes are regulated may provide insight into how we might intervene to facilitate and enhance them so that we might prevent or mitigate the devastating consequences of AKI...
  34. ncbi The contribution of adult stem cells to renal repair
    Benjamin D Humphreys
    Renal Division, Brigham and Women s Hospital, Department of Medicine, Harvard Medical School, Harvard Stem Cell Institute and Harvard MIT Division of Health Sciences and Technology, Boston, MA 02115, USA
    Nephrol Ther 3:3-10. 2007
    ..The identification of adult renal epithelial progenitor cells will ultimately determine the future direction of renal regenerative medicine...
  35. ncbi Renal stem cells in recovery from acute kidney injury
    B D Humphreys
    Renal Division, Brigham and Women s Hospital, Boston, MA, USA
    Minerva Urol Nefrol 58:329-37. 2006
    ..In this review we focus on our current understanding of the potential role of renal and extrarenal stem cells in repair of the adult kidney and highlight some of the controversies in this field...
  36. ncbi Urinary N-acetyl-beta-(D)-glucosaminidase activity and kidney injury molecule-1 level are associated with adverse outcomes in acute renal failure
    Orfeas Liangos
    Division of Nephrology, Caritas St Elizabeth s Medical Center, 736 Cambridge Street, Boston, MA 02135, USA
    J Am Soc Nephrol 18:904-12. 2007
    ..78 (95% CI 0.71 to 0.84) in predicting the composite outcome. Urinary markers of kidney injury such as NAG and KIM-1 can predict adverse clinical outcomes in patients with ARF...
  37. ncbi Mechanistic biomarkers for cytotoxic acute kidney injury
    Vishal S Vaidya
    Harvard Institutes of Medicine, Brigham and Women s Hospital, Harvard Medical School, Renal Division, Rm 550, 4 Blackfan Circle, Boston, MA 02115, USA
    Expert Opin Drug Metab Toxicol 2:697-713. 2006
    ..This review presents the current status of sensitive and specific biomarkers to detect preclinical and clinical renal injury and summarises the techniques used to quantitate these biomarkers in biological fluids...
  38. ncbi T cell, Ig domain, mucin domain-2 gene-deficient mice reveal a novel mechanism for the regulation of Th2 immune responses and airway inflammation
    Paul D Rennert
    Biogen Idec, 12 Cambridge Center, Cambridge, MA 01746, USA
    J Immunol 177:4311-21. 2006
    ..These studies show that TIM-2 is a novel and critical regulator of effector T cell activity...
  39. ncbi Induction of kidney injury molecule-1 in homozygous Ren2 rats is attenuated by blockade of the renin-angiotensin system or p38 MAP kinase
    Martin H de Borst
    Dept of Pathology and Laboratory Medicine, Univ Medical Center Groningen and Univ of Groningen, PO Box 30 001, 9700 RB Groningen, The Netherlands
    Am J Physiol Renal Physiol 292:F313-20. 2007
    ..01). Kim-1 is associated with development of RAS-mediated renal damage. Antifibrotic treatment through RAS blockade or p38 MAP kinase inhibition reduced Kim-1 in the homozygous Ren2 model...
  40. ncbi Mineralocorticoid receptor blockade confers renoprotection in preexisting chronic cyclosporine nephrotoxicity
    Jazmin Pérez-Rojas
    Molecular Physiology Unit, Instituto de Investigaciones Biomedicas, Universidad Nacional Autonoma de Mexico
    Am J Physiol Renal Physiol 292:F131-9. 2007
    ..In conclusion, MR blockade with Sp prevented the progression of renal injury in preexisting chronic CsA nephropathy. These results suggest that Sp may reduce CsA-induced established nephrotoxicity in patients...
  41. ncbi Renal stem cells in recovery from acute kidney injury
    B D Humphreys
    Renal Division, Brigham and Women s Hospital, Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
    Minerva Urol Nefrol 58:13-21. 2006
    ..In this review we focus on our current understanding of the potential role of renal and extrarenal stem cells in repair of the adult kidney and highlight some of the controversies in this field...
  42. ncbi Tubular kidney injury molecule-1 in protein-overload nephropathy
    Mirjan M van Timmeren
    Department of Pathology and Laboratory Medicine, University Medical Center Groningen and University of Groningen, Groningen, The Netherlands
    Am J Physiol Renal Physiol 291:F456-64. 2006
    ..These results implicate involvement of Kim-1 in the pathogenesis of proteinuria-induced renal damage/repair. Urinary Kim-1 levels may serve as a marker of proteinuria-induced renal damage...
  43. ncbi Mesenchymal stem cells in acute kidney injury
    Benjamin D Humphreys
    Renal Division, Brigham and Women s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
    Annu Rev Med 59:311-25. 2008
    ..This review summarizes current knowledge and identifies gaps in our understanding of MSC biology that will need to be filled in order to translate recent discoveries into therapies for AKI in humans...
  44. pmc Comparison of kidney injury molecule-1 and other nephrotoxicity biomarkers in urine and kidney following acute exposure to gentamicin, mercury, and chromium
    Yuzhao Zhou
    Center for Devices and Radiological Health, U S Food and Drug Administration, White Oak Life Sciences Laboratory, Silver Spring, MD 20993, USA
    Toxicol Sci 101:159-70. 2008
    ..Urinary Kim-1 and kidney Kim-1/Havcr1 expression appear to be sensitive and tissue-specific biomarkers that will improve detection of early acute kidney injury following exposure to nephrotoxic chemicals and drugs...
  45. pmc Reduction of proteinuria in adriamycin-induced nephropathy is associated with reduction of renal kidney injury molecule (Kim-1) over time
    Andrea B Kramer
    Department of Pathology and Laboratory Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
    Am J Physiol Renal Physiol 296:F1136-45. 2009
    ....
  46. ncbi HIF in kidney disease and development
    Lakshman Gunaratnam
    Renal Division, Department of Medicine, Brigham and Women s Hospital, Harvard Medical School, Boston, MA 02115, USA
    J Am Soc Nephrol 20:1877-87. 2009
    ..In this review, we discuss the mechanisms of oxygen sensing in renal cells and highlight the role of hypoxia and HIF activation under physiologic conditions and in renal development as well as in acute and chronic kidney diseases...
  47. pmc Role of cytosolic NADP+-dependent isocitrate dehydrogenase in ischemia-reperfusion injury in mouse kidney
    Jinu Kim
    Department of Anatomy and BK 21 Project, Kyungpook National University School of Medicine, Daegu, Republic of Korea
    Am J Physiol Renal Physiol 296:F622-33. 2009
    ....
  48. pmc Modulation of aquaporin-2/vasopressin2 receptor kidney expression and tubular injury after endotoxin (lipopolysaccharide) challenge
    Frederic Chagnon
    Groupe de Recherche en Physiopathologie Respiratoire, Centre de Recherche Clinique, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, QC, Canada
    Crit Care Med 36:3054-61. 2008
    ....
  49. pmc Effect of renin-angiotensin-aldosterone system inhibition, dietary sodium restriction, and/or diuretics on urinary kidney injury molecule 1 excretion in nondiabetic proteinuric kidney disease: a post hoc analysis of a randomized controlled trial
    Femke Waanders
    Department of Nephrology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
    Am J Kidney Dis 53:16-25. 2009
    ..We hypothesized that a decrease in proteinuria by using therapeutic interventions is associated with decreased urinary KIM-1 levels...
  50. pmc Immunolocalization of Kim-1, RPA-1, and RPA-2 in kidney of gentamicin-, mercury-, or chromium-treated rats: relationship to renal distributions of iNOS and nitrotyrosine
    Jun Zhang
    Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland 20993, USA
    Toxicol Pathol 36:397-409. 2008
    ..It is possible that iNOS activation with nitrotyrosine production in injured nephron segments may be involved in the induction of Kim-1, RPA-1, and RPA-2 following exposure to nephrotoxicants...
  51. pmc Kidney injury molecule-1 is a phosphatidylserine receptor that confers a phagocytic phenotype on epithelial cells
    Takaharu Ichimura
    Renal Division, Brigham and Women s Hospital, Harvard Institutes of Medicine, Room 550, 4 Blackfan Circle, Boston, Massachusetts 02115, USA
    J Clin Invest 118:1657-68. 2008
    ..Thus, KIM-1 is the first nonmyeloid phosphatidylserine receptor identified to our knowledge that transforms epithelial cells into semiprofessional phagocytes...
  52. ncbi Intrinsic epithelial cells repair the kidney after injury
    Benjamin D Humphreys
    Renal Division, Department of Medicine, Brigham and Women s Hospital, Harvard Institutes of Medicine, Room 550, 4 Blackfan Circle, Boston, MA 02115, USA
    Cell Stem Cell 2:284-91. 2008
    ..These results indicate that regeneration by surviving tubular epithelial cells is the predominant mechanism of repair after ischemic tubular injury in the adult mammalian kidney...
  53. pmc Biomarkers of nephrotoxic acute kidney injury
    Michael A Ferguson
    Division of Nephrology, Children s Hospital Boston, Hunnewell 319, Boston, MA 02115, United States
    Toxicology 245:182-93. 2008
    ....
  54. pmc High urinary excretion of kidney injury molecule-1 is an independent predictor of graft loss in renal transplant recipients
    Mirjan M van Timmeren
    Department of Pathology and Laboratory Medicine, University Medical Center Groningen and University of Groningen, The Netherlands
    Transplantation 84:1625-30. 2007
    ..Urinary KIM-1 excretion has been quantified as biomarker of renal damage. We prospectively studied whether urinary KIM-1 predicts graft loss, independent of renal function and proteinuria...
  55. pmc Kidney injury molecule-1 expression in transplant biopsies is a sensitive measure of cell injury
    P L Zhang
    Division of Laboratory Medicine, Geisinger Medical Center, Danville, Pennsylvania, USA
    Kidney Int 73:608-14. 2008
    ..KIM-1 expression is more sensitive than histology for detecting early tubular injury, and its level of expression in transplant biopsies may indicate the potential for recovery of kidney function...
  56. pmc Urinary biomarkers in the early diagnosis of acute kidney injury
    W K Han
    Renal Division, Department of Medicine, Brigham and Women s Hospital, Harvard Medical School, Boston, Massachusetts, USA
    Kidney Int 73:863-9. 2008
    ..Urinary MMP-9 was not a sensitive marker in the case-control study. Our results suggest that urinary biomarkers allow diagnosis of acute kidney injury earlier than a rise in serum creatinine...
  57. pmc Biomarkers of acute kidney injury
    Vishal S Vaidya
    Renal Division, Department of Medicine, Brigham and Women s Hospital, Harvard Medical School, Boston, MA 02115, USA
    Annu Rev Pharmacol Toxicol 48:463-93. 2008
    ....
  58. ncbi Urinary kidney injury molecule-1: a sensitive quantitative biomarker for early detection of kidney tubular injury
    Vishal S Vaidya
    Renal Division, Brigham and Women s Hospital, Harvard Medical School, 4 Blackfan Circle, Harvard Institutes of Medicine, Rm 550, Boston, MA 02115, USA
    Am J Physiol Renal Physiol 290:F517-29. 2006
    ....

Research Grants30

  1. Mechanisms of Atherogenesis in Insulin Resistance
    IRA A TABAS; Fiscal Year: 2013
    ..End of Abstract) ..
  2. KIM-1, microparticles and diabetic tubular injury
    Xueying Zhao; Fiscal Year: 2013
    ..Our studies will also shed light on KIM-1/KIM-MPs as attractive targets for kidney disease management. ..
  3. Expanding Excellence in Developmental Biology in Oklahoma
    Linda F Thompson; Fiscal Year: 2013
    ..abstract_text> ..
  4. Pacific NorthWest Regional Center of Excellence (PNWRCE)
    Jay A Nelson; Fiscal Year: 2013
    ..pseudomallei host pathogen response during both the septicemic as well as the intracellular phases of the disease. ..
  5. Meprin A Metalloproteinase in Acute Kidney Injury
    GUR PRASAD KAUSHAL; Fiscal Year: 2013
    ..The studies proposed in this application are aimed directly at understanding these mechanisms, which will result in appropriate therapeutic interventions. ..
  6. Northeast Biodefense Center
    W Ian Lipkin; Fiscal Year: 2013
    ..As a Center based in a School of Public Health and a State Department of Health, the NBC has a firm commitment to and practical understanding of Emergency Preparedness. ..
  7. Pathophysiology of Alveolar Epithelial Lung Injury
    Jacob I Sznajder; Fiscal Year: 2013
    ..The insights gained from the data generated from these studies will provide novel molecular targets for the development of new therapeutic strategies to treat patients with lung injury. ..
  8. Pacific Southwest RCE for Biodefense &Emerging Infectious Diseases Research
    Alan G Barbour; Fiscal Year: 2013
    ..abstract_text> ..
  9. FIBRINOGEN SIGNALING IN KIDNEY TISSUE REPAIR
    Vishal S Vaidya; Fiscal Year: 2013
    ..Understanding Fg signal transduction in kidney regeneration following kidney damage may provide opportunities for early diagnosis, prevention, and therapeutic interventions. ..
  10. Linking the physical and chemical characteristics of Qdots to their toxicity
    TERRANCE JAMES KAVANAGH; Fiscal Year: 2013
    ..These advances can then be used in safe design and manufacturing of nanomaterials so as to maximize their utility for many applications. ..