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Focus of Nephrology Research:

pathogenesis and treatment of glomerulonephritis and nephrotic syndrome
regulation of renal sodium and water transport
hypertension
acute kidney injury
chronic kidney disease
diabetic nephropathy
transplantation
hereditary nephritis
dialysis

Faculty Research Interests

Srinivasan Beddhu, M.D., Associate Professor of Medicine. Dr. Beddhu’s research focuses on nutrition and atherosclerotic disease in CKD. He is a member of the NKF K/DOQI guidelines on cardiovascular disease on dialysis patients. He has extensively used the USRDS and NHLBI pubic access databases. He is moving into interventional and translational studies of dialysis patients to address the same questions in more detail. His has studied the independent association of kidney disease with the hazard of myocardial infarction and the associations of obesity, malnutrition, serum albumin and inflammation with atherosclerosis in CKD as well as the association of obesity with inflammation in CKD. Drs. Samore and Cheung are co-investigators on studies on protein intake and dialysis outcomes, while Drs. Anderson, Greene, McClain and Cheung are co-investigators on studies on adipokine association with cardiovascular outcomes.

Wayne Border, M.D., Professor of Medicine. Drs. Border and Noble are interested in basic research focused on the molecular pathogenesis of progressive kidney disease. They have produced a large body of work showing that the cytokine transforming growth factor-ß (TGF–ß) is a major cause of tissue fibrosis in numerous experimental and human disorders. Their laboratory was the first to implicate TGF-ß in the pathogenesis of fibrosis in both glomerulonephritis and diabetic nephropathy. They were also the first to show the therapeutic effect of inhibiting TGF–ß in vivo with an antibody and the human protein decorin. They have also demonstrated that gene therapy could be used in a novel way to block fibrosis in a model of glomerulonephritis. Finally, they have recently shown the therapeutic benefit in blocking the in vivo actions of PAI-1 in a model of glomerulonephritis. Drs. Border and Noble are the major investigators in the Renal Fibrosis Institute.

Alfred Cheung, M.D., Professor of Medicine. Dr. Alfred Cheung’s research has two primary foci. The first is laboratory research where the efforts are directed towards the development of strategies to prevent hemodialysis vascular access stenosis using local drug delivery systems. The main strategy of this project is to employ drug delivery platforms that are thermosensitive (thus injectable), nontoxic, biodegradable (thus obviate surgical removal), and allow delayed release (thus allowing for wound healing after arteriovenous graft placement) and sustained release. One goal is to examine the efficacy and specificity of anti-proliferative drugs on both arterial and venous smooth muscle cells. The mechanism of actions of some of these drugs is also explored in cell culture models. A second goal is to develop polymers with characteristics that fulfill the specific requirements for the local delivery. A third goal to examine the pharmacokinetics of the perivascularly delivered drugs across native blood vessels and synthetic grafts in vitro, ex vivo and in vivo. A final goal is to examine the safety and efficacy of these strategies in experimental animal models of vascular access stenosis. This project utilizes many research techniques, including tissue culture, gel electrophoresis, high-performance liquid chromatography, PCR, autoradiography, immunoblotting and immunoassays, microarray, proteomics, polymer chemistry, in vitro vascular tissue models for pharmacokinetic studies, animal surgery, various histology techniques, 3-dimensional image reconstruction, vascular sonography, magnetic resonance imaging, mathematical modeling, statistical analysis and relational database.
            The second research focus of Dr. Cheung is clinical investigation related to chronic kidney disease and dialysis. Some of the ongoing projects are secondary analyses of the multicenter Hemodialysis trial (HEMO Study) sponsored by the NIDDK in which Dr. Cheung served as the P.I. of the Utah Clinical Center, analysis of the preserved plasma samples and data from an ancillary project of the HEMO Study examining lipids and lipoproteins which was initiated and organized by Dr. Cheung, and epidemiologic studies of cardiovascular risk factors in dialysis patients. Dr. Cheung has also organized and chairs a Kidney Disease Research Consortium, with the primary objective of conducting multicenter observational and interventional studies related to chronic kidney disease and dialysis. This consortium is currently comprised of 29 clinical centers which are mostly academic centers. Several projects are currently being planned with the consortium members. These clinical projects are fertile training opportunities for the clinical research fellows who are interested in epidemiology research involving large national databases, in-depth single-center or multi-center observational studies, and interventional trials.
Tom Greene, Ph.D., Professor of Medicine. Dr. Greene is the lead statistician on NIH-sponsored multi-centered trials and is very activity involved with study design. He works with Drs. Cheung and Leypoldt on follow-up analysis of the HEMO trial. He also works with Dr. Beddhu on analysis of the influence of dietary protein on outcomes in dialysis patients as well as the association of adipokines in dialysis patients with cardiovascular morbidity and mortality.

Yufeng Huang, M.D., Ph.D., Research Assistant Professor of Medicine. Dr. Huang studies plasminogen activator inhibitor-1 (PAI-1) involvement in glomerular disease. In particular, she investigates the role of PAI-1 in progression of diabetic nephropathy. She also studies the profibrotic actions of renin in kidney disease.

Bellamkonda Kishore, M.D., Ph.D., Research Associate Professor of Medicine. Dr. Kishore has more than 20 years of research experience in renal physiology, pathophysiology and drug toxicity. In renal physiology, his research interests are cellular and molecular mechanisms of vasopressin-independent regulation of renal medullary collecting duct water transport, with particular emphasis on the role of purinergic mechanisms, and the interaction of purinergic and prostanoid systems in the medullary collecting duct. The second are of research is the study of cellualr and molecular mechanisms of vasopressin-resistant polyruia of acute renal failure, with particular emphasis on the biology of the collecting duct. The third are of interest is the study of cellular and molecular mechanisms of tubulointerstitial reactions associated with certain forms of acute lysosomal storage conditions of proximal tubular cells, focusing on the induction of proliferation of erythropoietin-producting peritubular cells in the kidney. In addition, Dr. Kishore brings to the program the capability of perfusing isolated tubules.

Donald E. Kohan, M.D., Ph.D., Professor of Medicine. Dr. Kohan's laboratory studies two major areas. The first area is understanding the role of collecting duct-derived endothelin and nitric oxide in regulating systemic blood pressure and renal sodium and water excretion in health and disease. They have pioneered cell-specific gene targeting in the kidney using the Cre-loxP system and have used this technique to knockout components of the endothelin system selectively in principal cells of the collecting duct. Collecting duct endothelin-1 knockout mice are hypertensive and have impaired ability to excrete a sodium or water load. They have ongoing efforts to optimize cell specific knockout, including development of inducible knockouts (using Cre coupled to the ligand-binding domain of the estrogen receptor or the tetracycline transactivator) as well as improved integration site independent transgene expression. The technique of cell-specific gene targeting has recently been adapted by Dr. Kohan's laboratory to developing a mouse model of polycystic kidney disease.
            The other area of research in Dr. Kohan's laboratory involves understanding the mechanisms of cell injury in post-diarrheal hemolytic uremic syndrome. They have determined that renal tubular cells are highly susceptible to shigatoxin cytotoxicity, while endothelial cell sensitivity requires exposure to inflammatory cytokines. They have examined the molecular mechanisms controlling globotriaosylceramide (Gb3) expression (the major cognate shigatoxin receptor) and have determined that Gb3 synthase is a control site of Gb3 expression.

Ken Leypoldt, Ph.D., Research Professor of Medicine. Dr. Leypoldt's research explores new approaches for improving renal replacement therapies when treating end stage renal disease patients. The research encompasses several laboratory and clinical projects and includes the modalities of hemodialysis, hemofiltration and peritoneal dialysis. A major focus of his research examines the molecular kinetics and removal capacities of the different treatment modalities. Another major project in his laboratory examines the effect of peritoneal inflammation on the transport characteristics of the peritoneal membrane in animal models. This project aims to understand the relationship between peritonitis and permanent changes in peritoneal membrane structure and function.

Teri Jo Mauch, M.D., Ph.D., Associate Professor of Pediatrics, Division of Pediatric Nephrology. Dr. Mauch's laboratory investigates the roles of the vasculature and vasoactive peptides in embryonic kidney development. The first project investigates branching morphogenesis in cultured mouse metanephroi from the GFP-kidney mouse, (GFP is expressed under the control of the Hox b7 promoter) illuminating the ureteric bud and its derivatives, thereby facilitating real-time analysis of branching morphogenesis. Fetal kidneys cultured in vitro under conditions that either suppressed or drove AT2 mediated angiotensin II signaling showed that AT2 is important in patterning the ureteric bud. Current studies compare wild type with AT2-null mice, using microarray, quantitative PCR and in situ hybridization to identify downstream effectors of AT2 mediated angiotensin II signaling.
            The second project combines the avian model with the genetic power of mutant mice to define the molecular relationships between blood vessel formation, somitogenesis and pronephros induction. Dr. Mauch hypothesizes that molecules secreted by resident angioblasts regulate pronephros induction by the paraxial mesoderm. Studies include fate mapping to determine the relationship of angioblasts to paraxial and intermediate mesoderm precursors during gastrulation and tests to determine if angioblasts and vascular signals are necessary and sufficient for pronephros induction. Chemical manipulation (inhibitors of vasculogenesis and angiogenesis) and cut and paste tissue recombination experiments combining tissues isolated from knockout mice that lack blood vessels with chick intermediate mesoderm will determine if blood vessel precursors are required for pronephros induction by PM. To determine if the vasculature is sufficient to induce the pronephros, intermediate mesoderm will be co-cultured with arteries, vascular inducers.

Lance Miller, Ph.D., Research Assistant Professor of Pediatrics, Division of Pediatric Nephrology. Dr. Miller studies collecting duct salt and water transport as well as renal development. He investigates the regulation of amiloride-sensitive current by endothelin-1 in MPKccd14 and A6 cells using patch-clamp, open circuit analysis and immunoblotting. These experiments are to be extended to the isolated perfused collecting ducts from mice with the collecting duct-specific knockout of endothelin-1. Dr. Miller also collaborates with Dr. Raoul Nelson on the identification of collecting duct-specific transcription factors. He and Dr. Nelson developed transgenic mice which express GFP in either intercalated or principal cells. Using these mice, they have recently developed a technique for the automated isolation of large quantities of pure collecting duct for genomic, proteomic, functional analysis and establishing primary cell cultures. They are now developing a method to obtain pure intercalated and principal cells using fluorescence activated cell sorting and mice expressing DsRed fluorescent protein in principal cells and GFP in intercalated cells.

Raoul D. Nelson, M.D., Ph.D., Associate Professor of Pediatrics, Division of Pediatric Nephrology. Dr. Nelson studies regulation of gene expression within principal and intercalated cells of the collecting duct. Aquaporin-2 and the V-ATPase B1 subunit promoters have been coupled to GFP in transgenic mice to achieve principal and intercalated cell, respectively, -specific expression in vivo. Studies are underway to define the promoter elements and transcription factors responsible for cell specific gene expression. Fluorescent assisted microdissection and FACS are used to isolate collecting ducts, principal cells or intercalated cells from transgenic kidneys expressing GFP. In addition, transgenic kidneys expressing GFP are being used to develop cell culture systems. Dr. Nelson has identified candidate collecting duct specific transcription factor gene families. The epithelial Ets factors are the first group of collecting duct transcription factors under investigation. Real-time RT-PCR, in situ hybridization and immunocytochemistry are being used to define the expression of these factors in the adult and developing kidney. In addition, the reporter gene assays and chromatin immunoprecipitation assays are being used to examine the role of these factors in the regulation of collecting duct transporters such as aquaporin-2, epithelial sodium channel and V-ATPase. The epithelial Ets factors may be important in the differentiation and maturation of the collecting duct, and also potentially in diseases of the collecting duct.
            Knowledge about collecting duct specific gene expression is being used to develop principal and intercalated cell specific gene targeting systems. The aquaporin-2 promoter has already been used to drive expression of Cre recombinase in transgenic mice. These transgenic mice are being used to constitutively delete genes in principal cells. One such application that is currently underway is to delete PKD1 in principal cells of the collecting duct in attempts to develop a non-lethal mouse model of polycystic kidney disease. The V-ATPase B1 subunit promoter is currently being employed to drive the expression of Cre recombinase or rtTA intercalated cells of transgenic mice. These transgenic mice will be used to achieve constitutive and temporal regulated deletion of genes in the intercalated cells. One such application of this system will be to delete the V-ATPase in intercalated cells.

Nancy Noble, Ph.D., Research Professor of Medicine. Drs. Border and Noble are interested in basic research focused on the molecular pathogenesis of progressive kidney disease. They have produced a large body of work showing that the cytokine transforming growth factor-ß (TGF–ß) is a major cause of tissue fibrosis in numerous experimental and human disorders. Their laboratory was the first to implicate TGF-ß in the pathogenesis of fibrosis in both glomerulonephritis and diabetic nephropathy. They were also the first to show the therapeutic effect of inhibiting TGF–ß in vivo with an antibody and the human protein decorin. They have also demonstrated that gene therapy could be used in a novel way to block fibrosis in a model of glomerulonephritis. Finally, they have recently shown the therapeutic benefit in blocking the in vivo actions of PAI-1 in a model of glomerulonephritis. Drs. Border and Noble are the major investigators in the Renal Fibrosis Institute.

Fuad Shihab, M.D., Clinical Professor of Medicine. Dr. Shihab's laboratory studies mechanisms of fibrosis in nephrotoxicity of immunosuppressive drugs in transplantation. Animals models of chronic calcineurin inhibitors nephrotoxicity have been established. The involvement of vascular endothelial growth factor, connective tissue growth factor, and fibrogenic cytokines such as TGF-ß and plasminogen activator inhibitor-1 are investigated in these models. In addition, the composition of the extracellular matrix and the role of apoptosis in these disease entities are studied. The effect of angiotensin converting enzyme inhibitors, angiotensin receptor blockers and anti-fibrotic molecules such as pirfenidone on fibrosis are examined. The interactions of cyclosporine with other newer immunosuppressive drugs such as mycophenolate mofetil and sirolimus and the resultant effect on fibrosis and on the expression of fibrogenic cytokines and matrix proteins is also being investigated. Finally, applications of these findings are being carried to the clinical arena by studying the effect of different immunosuppressive strategies, such as corticosteroid withdrawal, on the expression of transforming growth factor as a means of predicting long-term renal allograft function.

Kevin Strait, Ph.D., Research Assistant Professor of Medicine. Dr Strait collaborates with Dr. Donald Kohan in studies of renal collecting duct salt and water transport as they relate to changes in signaling systems that are modulated by endothelin-1, adenylate cyclase and/or nitric oxide. Dr Strait also collaborates with Dr. Lance Miller on identifying the biochemical pathways involved in endothelin-1 regulation of ENaC channels in MPKccd14 cells, and in isolated perfused collecting ducts.

Christi M. Terry, Ph.D., Research Assistant Professor of Medicine. Dr. Terry has a Ph. D. in Pharmacology and Toxicology from the University of Utah. She collaborates with Dr. Alfred Cheung on the development of effective pharmacotherapies against hemodialysis arteriovenous (AV) graft stenosis. Approximately 50% of hemodialysis grafts fail in the first year after placement primarily due to stenosis which results from cell overgrowth into the lumen of the graft. An effective treatment for AV graft stenosis is currently unavailable. She utilizes a biopolymer gel for the targeted delivery of drug to the graft/vessel anastomoses. She is also interested in understanding how inflammatory cells such as macrophages and T-lymphocytes participate in hyperplasia development in hemodialysis grafts. She carries out studies on the role the foreign body response plays in the development of hyperplasia in hemodialysis grafts. She also collaborates with physicists, bioengineers and computer scientists to study the impact of flow dynamics on where hyperplasia forms within AV grafts, and more basically, how normal and aberrant flow alters vascular cell responses to drugs. These studies utilize magnetic resonance imaging (MRI) to examine hyperplasia development in vivo as well as measure flow dynamics over time. She interacts with the bioengineers and computer scientists also to model the pharmacokinetics of drug release from the polymer gel into tissue. She is also interested in using MRI to track macrophage recruitment into the AV graft over time. In the basic science realm, she investigates the effect of post-translational modifications such as glycosylation on the localization and activity of soluble epoxide hydrolase, an enzyme responsible for the catabolism of epoxyeicosatrienoic acids (EETs). EETs have anti-inflammatory and other effects in vascular cells and we are currently investigating the use of inhibitors of soluble epoxide hydrolase to prevent hemodialysis graft stenosis. The overall goal of her work is to understand the causes of hemodialysis graft stenosis and to develop effective treatments to prevent graft failure.

Florian Toegel, M.D., Ph.D. Research Associate in Medicine. Dr. Toegel’s current research interests include: 1) treatment of ischemic acute kidney injury (AKI) with novel cell based treatment approaches; 2) mechanism of action of mesenchymal stem cells in AKI; 3) role of the chemokine SDF-1 in the kidney after AKI; 4) homing mechanisms of stem cells in AKI; 5) clinical scale expansion systems for mesenchymal stem cells; 6) in vivo tracking of administered stem cell populations; and 7) influence of uremic environment on growth and differentiation properties of mesenchymal stem cells. He works closely with Dr. Westenfelder.

Christof Westenfelder, M.D., Professor of Medicine. The overall research focus of Dr. Westenfelder's research is on the pathophysiology and treatment of acute renal failure. There is a particular emphasis on the role of erythropoietin (EPO) in acute renal failure, which has been identified by Dr. Westenfelder as a renotropic cytokine. In addition, his group has found that EPO has additional importance in kidney cancer, polycystic kidney disease, acquired cystic kidney disease, and uremic encephalopathy. Besides the role of EPO in acute renal failure, Dr. Westenfelder has demonstrated that bone marrow-derived stem cells possess kidney specific plasticity (are able to differentiate into renal cells), and when administered to rats with acute renal failure, act renoprotectively (appear to function as kidney precursor cells. He closely collaborates with Dr. Toegel on the stem cell studies. Co-investigations with Dr. Kishore on the “Novel Induction of Erythropoietin-Producing Cells in the Kidney” are based on their discovery that a small polypeptide, poly-D-glutamic acid, when administered to a rat, results in a proximal tubular, noncytotoxic lysosomal storage condition that triggers a robust proliferative response of erythropoietin-producing peritubular fibroblasts. In addition, there are collaborations with Dr. Teri Jo Mauch investigating the expression of developmental genes in the acute renal failure kidney as well as in bone marrow-derived stem cells (e.g. Pax 2 and Pax 8).

Tianxin Yang, M.D., Ph.D., Professor of Medicine. Dr. Yang’s long term interests are the role of arachidonic acid metabolites and other lipid-derived products in regulation of renal function, related to sodium balance and blood pressure regulation. The current emphasis is on characterizing renal function of cyclooxygenase-2 (COX-2) and peroxisome proliferator-activated receptor gamma (PPARg) and thus there are two lines research: 1) Renal function of COX-2. COX-2 is expressed in distinct cell types in the kidney involved in regulation of a wide spectrum of renal functions. Macula densa COX-2 is induced by low salt and involved in regulation of renin secretion and vascular tone while renal medullary COX-2 is induced by high salt and possibly involved in promoting salt excretion and stabilizing blood pressure. Therefore, two series of studies are being pursued: a) Elucidation of the role and mechanism of COX-2 in regulation of renin secretion. This will be achieved by examining the interaction of COX-2 and nNOS in the macula densa cells. The interaction between the two pathways is examined in vivo using nNOS -/- and COX-2 -/- mice and in vitro using a mouse macula densa derived cell line; b) Investigation of the role and mechanism of high salt-induced renal medullary COX-2 expression in regulation of sodium balance and blood pressure. Chronic intramedullary infusion techniques are currently used to examine whether site-specific COX-2 inhibition in renal medulla produces salt sensitive hypertension. Interactions between renal medullary COX-2 with other local factors, such as nitric oxide and endothelins, are also being examined. 2) Renal and vascular functions of PPARg. PPARg is a novel nuclear receptor, controlling expression of a range of target genes through interaction with PPAR responsive elements. PPARg ligands (thiazolidinediones) cause edema due to with fluid retention, yet the mechanism is not fully known. Knockout of PPARg in the collecting duct abrogates the fluid retention; these knockout mice are being used explore the molecular mechanisms of PPARg in regulation of sodium balance and blood pressure.