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The Bonventre Laboratory of Kidney Injury and Repair

Pathophysiology of Kidney Tubular Injury and Chronic Fibrosis

A major focus of the laboratory has been the study of the pathophysiology of acute renal failure and processes involved with repair. There are many parallels between repair and the normal development of the kidney. While repair is generally considered to be adaptive it can be maladaptive, especially when the acute injury is superimposed on chronic kidney disease. Hence the large effort that has gone into understanding developmental systems will potentially translate into therapeutic approaches to treatment of adult as well as pediatric renal diseases. As a result of our experiments we have placed inflammation at the core of the pathophysiology and are continuing to explore the role of inflammation in the pathophysiology of acute renal injury and ways in which we can interrupt this response and reduce injury. We have found two proteins, KIM-1, an epithelial protein and nmb, a macrophage protein, which we believe play critical roles in the response of the kidney and have created a Kim-1 knockout/Gal4 knockin animal which will potentially allow us to use the characteristics of the promoter region of Kim-1 to express proteins specifically in the S3 segment of the proximal tubule, where most of the injury occurs. In addition we want to understand the factors determining the recovery of the kidney in order to design strategies to enhance and hasten the processes necessary for recovery. These latter goals necessitate multiple experimental approaches. My laboratory carries out whole animal experiments on normal or knockout animals in order to test potential pharmacologic treatments or to test the hypothesis that a particular protein is important to the injury or repair process. More recently we have established models of preconditioning in the mouse in which we have uncoupled exposure to ischemia from the normal functional consequences of ischemia. We are employing genomic approaches to identify genes whose expression patterns might explain the profound protection we can induce in these models. We are using blood and urine proteomic approaches to identify new biomarkers and targets for therapy. Current studies have focused on genetic mouse models and zebrafish and include the role of stem cells in the repair process of the kidney post-ischemia.

Kidney Stem Cells

Kidney possesses the intrinsic capacity for repair after injury but whether adult kidney stem cells are responsible for epithelial regeneration is unresolved. During nephrogenesis, renal epithelia develop from precursors located in the metanephric mesenchyme that condense to form the nephron. Persistence of such cells in the adult could constitute a stem cell niche available for repair of damaged kidney. We evaluated the potential role of bone marrow derived stem cells in repair and concluded that these cells do not play a major role as precursors of the new epithelial cells with repair although they may have significant paracrine roles. Attention is now focused on the identification of intrarenal stem/precursor cells that may participate in repair. Genetic lineage approaches are in place and have provided a great deal of insight into the source of the cells that replace the dead cells. Other experiments are devoted to defining the factors responsible for directing embryonic stem cells down the kidney lineage. Bioengineering approaches are employed to understand the optimal cell-environmental interactions that optimize kidney cell differentiation in vitro to develop kidney assist devices and in vitro approaches to kidney toxicity prediction.

Biomarkers

Reliance on current measures of renal dysfunction, such as serum creatinine and blood urea nitrogen, has contributed to the slow translation of basic science discovery to therapeutically effective approaches in clinical practice. Insensitivity of commonly used biomarkers of renal dysfunction not only prevents timely diagnosis and estimation of injury severity, but also delays administration of putative therapeutic agents. We have cloned and characterized Kidney Injury Molecule-1 (KIM-1) as a very sensitive and specific biomarker of proximal tubular injury in a variety of species including man. The role of KIM-1 in the injured kidney is being explored using genetic and cell biological approaches and the role of this biomarker in a large number of kidney diseases in rodents and man is being evaluated. The laboratory serves as a Biomarker Core facility evaluating a number of urinary proteins that have been identified that potential sensitive and specific biomarkers for kidney injury. Further characterization of these candidate biomarkers will clarify their utility and define new diagnostic and prognostic paradigms for AKI, facilitate clinical trials and lead to novel effective therapies. Thus, we are positioned to soon have clinically useful biomarkers which, either alone or in combination, will facilitate earlier diagnosis, earlier targeted intervention, and improved outcomes.

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