Jeffrey H. Miner, PhD, professor of medicine

Cover Illustration JASN 27 (7)2013 Miner Lab

October 2011
Organogenesis Forum
Jianghui Hou PhD

February 2013
Organogenesis Forum
Jeffrey Gimble MD PhD

 

Highlights of research currently being conducted in the Division - including that by postdoctoral fellows - follows. Some of the investigators have primary appointments in other divisions within the Department of Internal Medicine or in other departments, reflecting the wide network of collaborative pursuits.

Washington University Kidney Translational Research Core

The Washington University Kidney Translational Research Core (KTRC) was established in 2007 by combining several existing Washington University databases. With support from the Washington University George M. O'Brien P30 Center, Renal Genes Growth Factors Development & Disease (2007-2012) it grew steadilty and now houses a state-of-the-art centralized kidney disease repository for clinical information and biological specimens from a growing cohort of 3000+ consented patients with renal diseases of interest to an international research base. These include acute kidney injury (AKI), glomerular diseases, chronic kidney diseases, renal cancer, cystic kidney diseases, transplant and its outcomes and congenital malformations. Core personnel assist investigators with regulatory approvals for conducting human studies, in study design and statistical support. The KTRC provides well-annotated, high quality clinical data and associated biospecimens encompassing a wide spectrum of renal diseases. Investigators conducting prospective studies leverage KTRC expertise and resources in enrollment, data management and infrastructure. The KTRC employs informatics with role-based security privileges accesible through the internet to integrate clinical data and biospecimens encompassing different kidney diseases. The KTRC integrates new technologies to accelerate translational research. It enhances multiple time point data and specimen collections and donor enrollments, and will create a bank of iPS cells from patients with glomerular diseases. With continued expansion of the database it will be even more valuable. Ther Director of the KTRC is Dr. Sanjay Jain. To access the Washington University Kidney Translational Research Core , please click on
WU Kidney Translational Research Core


Organogenesis Forum

The Washington University Renal Division sponsors & publishes four conferences per year in Organogenesis, a peer-reviewed journal produced by Landes Bioscience. The conferences are presented by leading international figures in renal biology. The publications constitute a special feature of the journal, the Organogenesis Forum. Visits of Organogenesis Forum speakers to Washington University have promoted scientific interchange between speakers and a broad cross section of the St. Louis Scientific Community both within and outside of Washington University. Visits have invigorated old and spawned new collaborations. To access a list of speakers, conferences and publications, please click on
Organogenesis Forum



Daniel W. Coyne, MD, professor of medicine, director of hemodialysis and outpatient clinics

 

 

Cover Illustration Organogenesis 7(3) 2011 (Hammerman lab)

 

Cover Illustration JASN 18:8:2007
(Miner Lab)

 

Institutional NIH Training Grants: Renal Disease

In 1961 and again in 1974, the Division was awarded an institutional training grant by the NIH to prepare selected candidates for full-time careers in academic medicine. Since that time, the postgraduate education of a large number of physicians and renal scientists has been supported by this grant. Most trainees have remained in academic medicine and many have gone on to head renal divisions in the United States, Canada, Europe, and Asia or to assume other important academic scientific and administrative positions. Drs. Neal Bricker and Saulo Klahr have served as principal investigators for this award. Dr. Marc R. Hammerman is the present principal investigator.

Renal Division-Biotechology Interactions

Rarely has there been a time when universities and industry have sought closer alignment than today. The biotechnology revolution that has transformed and continues to change the landscape of health care began at the benches of university scientists. It became a reality, however, through partnerships with visionary companies that understood the enormous potential of biotechnology. The Renal Division interacts with a number of biotechnology companies through research agreements, licensing agreements and clinical trials.

Transplantation of Developing Organs - Organogenesis of Kidney or Endocrine Pancreas

Marc R. Hammerman, MD

Human kidney or pancreas transplantation (or islet transplantation) is limited by organ availability. Use of porcine donors (xenotransplantation) is a possible alternative. One problem with the use in humans of developed porcine organs such as kidney or pancreas, is that humoral rejection is directed against antigens present on the vascular endothelium. Organ primordia (kidneys or pancreas) can be transplanted in 'cellular' form so that they develop in situ and become vascularized by the host obviating humoral rejection. If transplanted with its ureteric bud attached, a renal primordium (metanephros) transplanted into the mesentery enlarges and differentiates into a functional kidney that can maintain life for a time in otherwise anephric hosts following ureteroureterostomy between transplant and host. If transplanted at a sufficiently early stage of development, pancreatic primordia undergo selective endocrine differentiation post-transplantation such that exocrine components are not present at all. Embryonic pig pancreatic primordia transplanted into rats with type 1 (streptozotocin) or type 2 (ZDF) diabetes or into non-human primates with streptozotocin diabetes engraft and differentiate into functioning beta cells without the need for host immunsuppression. Glucose tolerance is normalized in rats with type 1 or type 2 diabetes within weeks after transplantation of pig pancreatic primordia.

Retro-peritoneal dissection of E15 rat embryo showing mesonephroi & metanephroi (Am. J. Physiol. 262:F523-F532, 1992)


Cover illustration, Kidney International 54:1, 1998 (Hammerman laboratory)

 

Cover illustration, Genomics 61:2, 1999 (Miner laboratory)

 

Cover illustration, Am. J. Physiology: Renal Physiology 48:1, 2000 (Hruska laboratory)

David Ornitz MD PhD, Alumni endowed professor, developmental biology


Cover Illustration, Developmental Cell. 22:6, 2012 (Kopan, Ornitz laboratories).

 

 

Vitamin D, Phosphate, and PTH Interactions in Health and Chronic Renal Failure

Eduardo Slatopolsky, MD

The major focus of our group is the evaluation of the factors involved in the pathogenesis of secondary hyperparathyroidism and bone disease in chronic renal failure. Our research examines the effect of dietary phosphate on the development of secondary hyperparathyroidism and, using the rat model of chronic renal failure, regulation of PTH secretion and pre-pro-PTH mRNA expression. In addition, new non-calcemic analogs of calcitriol are being investigated as regulators of PTH secretion and parathyroid gland growth in chronic renal failure. We are also interested in characterizing the mechanisms involved in the selective action of vitamin D analogs in vivo. Currently our laboratory is involved in studies delaying the progression of renal failure by controlling inflammation and oxidative stress. The basic research in the field of secondary hyperparathyroidism is complemented by a series of clinical projects.

Fibroblast Growth Factor Expression and Action

David Ornitz, MD, PhD

We use transgenic mouse models to study in vivo functions of Fibroblast Growth Factor (FGF) signaling and their interactions with other signaling pathways, to study mechanisms of organogenesis and apply our knowledge of developmental processes to understand mechanisms regulating tissue (skin, heart, lung, bone, inner ear, kidney) homeostasis, tissue repair in response to injury, and cancer. Genetic inactivation of endothelial FGF receptors prevents chemical-induced skin carcinogenesis, worsens wound healing, and worsens the heart's response to ischemia-reperfusion injury. FGF, Wnt and BMP signaling pathways interact to regulate growth of the lung and the complex process of branching morphogenesis. Micro RNAs regulate Fgf9 expression in the pathogenesis of Pleuropulmonary Blastoma, a pediatric lung cancer syndrome. FGF signaling activates adult lung progenitor cells in models of adenocarcinoma and response to injury. We are investigating how FGF signaling regulates osteoblast function and bone density. We are investigating how FGF signaling regulates proliferation of sensory progenitor cells and subsequent patterning of the cochlear sensory epithelium. Mice without FGF20 are profoundly deaf and in some cases have small kidneys. Mice lacking FGF9 have defects in development of the male urogenital tract and die after birth due to defects in lung development. Mice lacking both FGF9 and FGF20 have no kidneys. In mice, FGF9 appears to compensate for a total loss of FGF20. However, in humans FGF9 is not enough to rescue the kidney if FGF20 is missing.

Clinical Studies of PKD

Seth Goldberg, MD

With a prevalence of 1 in 400, polycystic kidney disease is among the most common life-threatening or organ-threatening genetic disorders. Despite the dramatic advances in our understanding of the disease at a molecular level, the development of successful therapies in delaying cyst growth and kidney failure have remained elusive. Our on-going clinical research is focused on improving the care of patients with PKD by attacking the problem from two approaches. First, we seek to identify clinical risk factors that are associated with more rapid disease progression, and such a study is currently underway. An improved understanding would then allow for targeted lifestyle modifications in addition to defining a sub-group of patients who may be more likely to benefit from therapy once such treatments become available. Second, we are actively involved in researching the efficacy and safety of novel therapeutic agents that have the potential to revolutionize the treatment of PKD. While our center’s transplant department allows for a smooth transition for patients with advancing disease, our expectation is that we will soon have the ability to slow or entirely halt the progression of PKD such that patients can retain independent kidney function throughout their lives. Our participation in multi-center randomized controlled clinical studies keeps us on the leading edge of these advances.

KIDNEY TRANSPLANTATION AT Barnes-Jewish Hospital/Washington University


 

Brent W. Miller, MD, professor of medicine

George Jarad MD, assistant professor of medicine

Ewelina Betleja PhD, postdoctoral fellow

Mansumeet Singh MBBS, postdoctoral fellow

Research in Renal Transplantation

Daniel C. Brennan, MD

Viral infections with cytomegalovirus (CMV) and polyoma (BK) virus remain major causes of morbidity and mortality in renal transplantation. We have performed several randomized prospective trials of over 700 patients to monitor CMV and BK and develop treatment and prophylaxis strategies. In collaboration with Dr. David Wang in the viral discovery group, we have also discovered two new human polyomaviruses. We continue to investigate novel immunosuppressive strategies. We pioneered the use of rabbit-antithymocyte globulin (Thymoglobulin) as an induction agent in the US. This agent was associated with a 10 –fold decrease in acute rejection rates at our center and improved long term outcomes. We perform outcomes and pharmacoeconomic research using local data and national data from the USRDS to determine risk factors for viral disease, to assess transplant outcomes, and to design cost-effective treatment. We are also active in industry and NIH sponsored clinical trials. Current trials are: 1) investigating a novel tacrolimus preparation to reduce the incidence of tremor, 2) use of a novel Jak-3 inhibitor to reduce the incidence of rejection, 3) use of low-dose tacrolimus and everolimus to limit calcineurin toxicity, 4) use of eculizumab to prevent antibody mediated rejection in HLA-incompatible transplants, and 5) the long-term follow up of the ITN-Edmonton protocol for islet transplantation.

Clinical Studies in Glomerular Diseases

Tingting Li, MD

Glomerular diseases are a well-recognized cause of chronic kidney disease and end-stage renal disease. These disorders are frequently associated with significant morbidity and mortality due not only to organ damage from the disease process itself, but also toxicities of therapeutic agents, in addition to the much increased risk of cardiovascular mortality. Our clinical research is focused on the development of safer and more effective therapies for glomerular diseases while exploring the underlying disease mechanisms, with the goals of improving disease remission rates, long-term kidney outcomes, as well as overall patient outcomes. Ongoing trials investigating the efficacy and safety of new therapeutic agents/regimens in lupus nephritis and ANCA-associated vasculitis are underway.

Nocturnal (Frequent) Dialysis Modalities

Brent W. Miller, MD

The Frequent Hemodialysis Network trial will evaluate frequent or ‘nocturnal’ hemodialysis. We were one of the early adapters of nocturnal hemodialysis in the United States and one of the first to use a form called “single-needle nocturnal hemodialysis” which improves patient safety and acceptance of the dialysis procedure.


 

Anitha Vijayan, MD, professor of medicine

 

 

Stanley Misler, MD, PhD associate professor of medicine

 

Masato Hoshi PhD, postdoctoral fellow

Ana Rossi, MD, postdoctoral fellow in transplantation

 

Acute Kidney Injury Cinical Trials

Anitha Vijayan, MD

Acute kidney injury is extremely common in the critically ill patient and is associated with a mortality of approximately 50%. We were one of centers in the NIH funded ATN study that was completed in 2008, which addressed the role of intensive renal replacement therapy in the treatment of AKI. The NIH-ATN study was the largest AKI study in the United States and we were one of the top 2 centers in enrollment. We are conducting several clinical trials addressing diagnostic and management strategies in AKI. Biomarkers for early detection is key in evaluating therapeutic agents and we are currently studying the role of NGAL in AKI. Early treatment of sepsis is crucial to improving outcomes in AKI and we are studying the role of polymyxin cartridge and hemoperfusion in the setting of endotoxemia. Other trials evaluating innovative CRRT technologies are also underway.

Management of Anemia and Secondary Hyperparathyroidism in CDK

Daniel W. Coyne, MD

Our research explores strategies to optimize management of anemia and secondary hyperparathyroidism in patients with chronic kidney disease while reducing costs. We have led and participated in multicenter trials demonstrating the efficacy and cost effectiveness of iron therapy in anemia management in dialysis and non-dialysis patients. We are also leading a multicenter trial exploring the efficacy and safety differences among different forms of active vitamin D in the treatment of secondary hyperparathyroidism. In addition to our group designing and participating in multicenter clinical trials, we collaborate with faculty in other clinical departments who are interested in examining diseases affecting patients on dialysis or with chronic kidney disease.

Medicine in Emerging Countries - Eritrea and Bhutan

David W. Windus, MD

Our work in Bhutan and Eritrea is conducted in conjunction with a team of nurses and diabetes educators and sponsored by Pathologists Overseas. The goals the Pathologists Overseas projects are improved physician education in management of chronic adult diseases and improved utilization of laboratory services. Specifically, we have developed productive working relationships with local physicians and other healthcare professionals, consulted on patients both in outpatient and inpatient settings, and organized continuing medical education courses for physicians in the areas of hypertension, diabetes, and kidney disease. We have evaluated the impact of the educational process on diabetes control in Eritrea. We demonstrated a significant improvement in diabetes control as evidence by a significant fall in hemoglobin A1C values. Our next project will be to further understand complications of diabetes in Eritrea by introducing urine microalbumin testing. The study will further expand knowledge about the prevalence of renal complications of diabetes in a new population but also allow for evidence-based interventions to slow the development of chronic kidney disease.

RET-mediated PLC-gamma activation ensures that only a single ureteric bud is formed.


Feng Chen PhD, associate professor of medicine and cell biology and physiology

Anubha Mutneja MBBS, postdoctoral fellow

 

 

Calcineurin in the Development of the Excretory System

Feng Chen, PhD

Our laboratory studies the genetic determinants and molecular mechanisms of development and diseases in the kidney and other urogenital organs. We have been using a variety of molecular genetic methods to create experimental and disease models to study the normal and abnormal development of the kidney and other urogenital organs with a specific focus on genes in the calcineurin/NFAT, TGFß/BMP, and Wnt signaling pathways. Congenital anomalies of the kidney and the urinary tract (CAKUT) constitute approximately 20 to 30 percent of all anomalies identified in the prenatal period and are important causes for renal failure in pediatric patients. Besides studying the pathogenic mechanism of CAKUT, we have been using forward genetics methods to reveal the hereditary determinants of these anomalies. Another research area is in glomerular development and diseases. We have created conditional cell ablation or gene inactivation/activation models to study the pathogenesis of glomerulosclerosis. We are in the process of using a multi-disciplinary approach, including cutting edge genome technologies to study the molecular mechanism leading from defined genetic changes to the development of benign and malignant diseases in urogenital organs. In addition to answering specific questions with clinical relevance, we are also keen on developing new genetic tools for the research community, such as new tissue-specific Cre transgenes and conditionally controllable transgenic lines.





Smad 4 inactivation in the ureteric mesenchyme at E16.5 leads to obstaruction secondary to smooth muscle defects by E18.5



Dr. David Windus (second from right), with other healthcare professionals from the Hospital in Thimphu, Bhutan




Moe R Mahjoub, PhD, assistant professor of medicine

Cover Illustration Proc. Natl. Acad Sci 105:3:2008
(Shaw Laboratory)

Bhavani Adusmilli MBBS, postdoctoral fellow

 

David Windus, MD, professor of medicine

Angelina Edwards MD, postdoctioral fellow in transplantation

Giselle Kohler MD, postdoctioral fellow

 

Centrosomes and Cilia: Signaling 'hubs' During Development and Disease

Moe R Mahjoub PhD

The focus of research in our laboratory is to understand how two intimately related cellular organelles, the centrosome and cilium, organize signaling pathways that control essential cellular functions. These highly conserved organelles act as signaling hubs that regulate diverse aspects of cell-cycle progression, cell differentiation, polarity, and migration. At the core of the centrosome is a pair of microtubule-based structures called centrioles, which are surrounded by an amorphous mix of proteins called the pericentriolar matrix. Centrioles play a critical role in cells by serving as basal bodies that nucleate the formation of the primary cilium. Except for a few specialized cell types, almost every cell in the human body contains a primary cilium. Defects in the structure and function of centrosomes and cilia lead to a range of human disease phenotypes known collectively as“Ciliopathies”. These include developmental defects such as polycystic kidney disease, nephronophthisis, polydactyly, infertility, hydrocephalus and cancer, as well as neurocognitive defects including mental retardation and dyslexia. We employ genomic, proteomic, biochemical and cell biological methods to delineate the regulation of centrosome-cilium assembly and function. We have recently identified a set of proteins involved in the assembly and maturation stages of centriole biogenesis. We also determined the cellular consequences of defects in the regulation of this protein complex, which leads to defective ciliary signaling causing abnormal cell division, polarity and migration. Current experiments are focused on (1) elucidating the molecular mechanisms of protein trafficking and localization to cilia; (2) proteomic approaches to identify regulatory proteins involved incentriole assembly, duplication and ciliogenesis; (3) examining the consequences of abnormal centrosome and cilium function in human disease, with particular emphasis on the development of ciliopathies affecting the kidney, such as polycystic kidney disease, nephronophthisis and cancer.

Laminin beta 2 missense mutations and ER stress

Ying Maggie Chen MD, PhD

All strata of the glomerular capillary wall including the glomerular basement membrane (GBM), podocytes and endothelial cells operate in a synchronic and integrated manner to maintain the integrity of the glomerular filtration barrier (GFB). Defects in the GFB may cause proteinuria. LAMB2 is a component of laminin-521, the major laminin in the mature GBM. Truncating or missense mutations in LAMB2 cause Pierson syndrome, which is characterized by congenital nephrotic syndrome, microcoria and other extrarenal manifestations. We have demonstrated that the R246Q mutation causes nephrotic syndrome by impairing secretion of laminin-521 from podocytes into the GBM. Furthermore, we have found that the C321R mutation results in defective secretion of C321R-LAMB2 and activates ER stress signaling pathways. Currently, we are using a combination of stably transfected cell lines, transgenic and knock out animal models, biochemistry and imaging techniques to delineate the individual ER stress-related pro-survival and pro-apoptotic signaling pathways and investigate possible therapeutic applications. Angiopoietins are a family of vascular growth factors. Ang-1 is a 70-kDa glycoprotein secreted by podocytes and activates endothelial tyrosine kinase receptor Tie2 in glomeruli. Ang-1/Tie2 signaling plays an important role in endothelial cell (EC) survival and EC-pericyte stabilization in response to microvascular stress. By utilizing inducible glomerular- or renal tubular-specific transgene system we are investigating how the locally altered ratio of Ang-1/Ang-2 affects a variety of kidney diseases in animal models.

Signal Transduction in Kidney and Bone

Keith A. Hruska, MD

Kidney disease is associated with loss of phosphate balance, skeletal anabolism and vascular smooth muscle differentiation. The laboratory has contributed fundamental mechanistic studies to the role of phosphorus as a cardiovascular risk factor. The mechanisms of renal injury producing loss of skeletal anabolism are recent discoveries of the laboratory and current focus of intense research. The discovery that kidney disease rapidly increases vascular smooth muscle cell motility and loss of contractile phenotype is a current focus of mechanism discovery. We have discovered the clinical effect of the vascular toxicity of renal injury as vascular stiffness contributing to the hypertensive actions of kidney disease. The laboratory currently utilizes human aortic vascular smooth muscle cells and several transgenic mouse translational models as experimental systems to explore the role of kidney injury and the skeleton in the multiple organ system failure of chronic kidney disease. Another goal is to understand the role of bone morphogenetic protein-7 (BMP-7) in kidney disease. BMP-7 is an early developmental morphogen in multiple systems including the kidney. In the adult organism, BMP-7 is a differentiation factor in the collecting duct and the glomerular podocyte. Chronic kidney disease decreases BMP-7 expression, and the loss of differentiation stimulus is disease permissive. We have found that BMP-7 administration is efficacious in the renal osteodystrophy, and vascular calcification of chronic kidney disease besides resisting renal disease progression. The concept of stimulating cellular differentiation to resist disease is a focus of the laboratory.

Fused podocyte foot process in mice with a targeted mutation in the laminin beta 2 gene.


 

 

Cover Illustration J Cell Sci 121:2008 (Miner lab)


Cover Illustration, J. Am. Soc. Nephrol. 21:4, 2010 (Miner lab).

 

 

Studies of Extracelular Matrix

Jeffrey H. Miner, PhD

A major interest of my laboratory is the role of basement membrane components in kidney function and disease, with particular emphasis on the glomerular basement membrane (GBM) as a component of the glomerular filtration barrier to albumin. Several genetic and acquired diseases of the kidney affect the GBM, causing thinning or thickening. We are focusing on the laminin and type IV collagen components of the GBM that are mutated in Pierson syndrome (a congenital nephrotic syndrome) and Alport syndrome (hereditary glomerulonephritis), respectively. We have produced knockout mice lacking relevant laminin or collagen IV chains to determine their functions in the kidney and elsewhere. We have also generated transgenic mice expressing mutant versions of laminin beta2 to understand why the mutations cause human kidney disease. Another aspect of my research concerns the role of cell-cell junction/polarity proteins in urogenital development. We have generated mice lacking proteins associated with the Scribble complex (including Scribble, discs large 1, and CASK) and find interesting developmental anomalies, including renal hypoplasia or agenesis and defects in maturation of the distal ureter and its connection to the bladder. These defects are observed in human congenital anomalies of the kidney and urinary tract (CAKUT). We are using state of the art methods to investigate the mechanisms for these defects and to determine whether mutations in these genes are involved in human CAKUT.

The Developmental Consequences of RET Dysfunction in Kidney.


 

 

Sanjay Jain MD PhD, associate professor of medicine and pathology

 

Cover Illustration Biol. of Reproduction 74:2:2006
(Jain Laboratory)

Jianghui Hou PhD, assistant professor of medicine.

 

Nima Naimi DO, postdoctoral fellow

 

Ying Maggie Chen MD PhD, assistant professor of medicine

Role of RET in development and diseases of the urinary tract

Sanjay Jain, MD, PhD

The goal of my laboratory is to elucidate how molecular and genetic signals during development regulate pathogenesis of pediatric and adult diseases of the kidneys and the lower urinary tract. We have used GFL-RET signaling as a paradigm and delineated novel concepts in the specification of the genitourinary and nervous systems. These studies have provided insights into pathogenesis of congenital defects such as renal malformations and Hirschsprung disease (intestinal aganglionosis). Currently we are employing interdisciplinary approaches in developmental biology, pathophysiology, genomics and bioinformatics to discover and determine how changes in the genome cause congenital and adult urinary tract diseases. We have generated a battery of conditional and reporter mouse strains to study early urinary tract development and reparative process in acute kidney injury. We are investigating the molecular signals in the nervous system that determine proper development and function of the kidneys and the lower urinary tract. We are deciphering signals in the nervous system that determine pathogenesis and responses to injury such as ischemia or inflammation in the urinary tract. We are delineating genomic alterations in patients with urinary tract defects using modern next-generation sequencing applications such as multiplexed targeted exome sequencing. We are using the results from the above approaches to design and develop assays for medical sequencing in kidney diseases. We believe our integrated approaches and resources will lead to a better understanding of genetic and molecular causes of diseases affecting the urinary tract and will aid in developing novel diagnostic and therapeutic modalities and in assessing prognosis.

Claudin function, interaction, and modulation of ion selectivity of tight junction

Jianghui Hou, PhD

The traditional view of the renal reabsorption process is that of a tandem array of ion channels and transporters located in the cell plasma membrane conducting ion transport in a coordinated manner at the expense of energy. Evidence accumulated during the last decade supports the existence of a previously unrecognized, yet pivotally important mechanism by which the kidney utilizes the cell-cell junctions to conduct ion transport, known as the paracellular pathway. Deregulation of the paracellular channels in the kidney results in a broad range of diseases such as hypomagnesemia, hypercalciuria, kidney stone and hypertension. My laboratory is interested in understanding the physiology of paracellular permeation of ions and solutes in the kidney. To this end, we have studied three important genes: Claudin or CLDN14, -16 and -19, all of which are genetically mutated in human hypercalciuric syndrome and kidney stone diseases. We have identified a novel pathway in the kidney that utilizes CLDN4 and CLDN8 to transport Cl- and regulate blood pressure. Using lentiviral transgensis, knockout and knockin recombination techniques, we have generated a series of transgenic mouse lines to mimic human conditions: CLDN16 knockdown, CLDN19 knockdown, CLDN14 overexpression, CLDN4 knockout and CLDN8 knockout. Using a number of genetic and biochemical analyses, we have revealed selective claudin protein interactions in the kidney that underpins the pathogenesis of hypercalciuria and kidney stone. We have uncovered a novel microRNA based mechanism for claudin gene regulation in the kidney. Most importantly, we have developed a run of techniques to record the paracellular channel in vitro in cultured renal epithelia and in vivo in perfused mouse kidney tubules. Ongoing projects are focused on (1) defining the heteromeric channel properties of claudin complex; (2) studying the renal handling of electrolytes in claudin KO mice; (3) deciphering the signaling pathway of CaSR-microRNA and its role in Ca++ related diseases.


 

Laura Hesemann MD, postdoctoral fellow

Siddiq Anwar MBBS, postdoctoral fellow

 

Treatment of Resistant and Unconrolled Hypertension (Rheos Trial)

Marcos Rothstein, MD

Dr. Rothstein is Principal Investigator for the Rheos Trial for the treatment of resistant and uncontrolled hypertension. This study involves the implant of an electrical stimulator at the carotid baroreflex sinus. With the feasibility trial in its fourth year, most patients have achieved sustained reductions in systolic BP over 25 mm Hg, along with significant left ventricular function improvement. A large multi-center randomized trial is underway and CKD patient sub-studies are in the planning stage.

Prevention of Complications in Patients with Chronic Kidney Disease

James A. Delmez, MD

We maintain an active collaborative clinical research agenda. These activities include determining that cinacalcet treatment during dialysis treatments is associated with an increased, not decreased, incidence of hypercalcemia and parathyroidectomy following renal transplantation. Also, we are participating in a multicenter study to determine if the enzyme, elastase, administered to the anastomosis of newly created fistulae will improve access flow rates and the likelihood of successful maturation. In collaboration with Dr. Eduardo Slatopolsky, we are investigating the relationships of serum parathyroid hormone, FGF-23, Klotho and other clinical variables in patients treated with chronic hemodialysis. The results should expand our knowledge of the pathophysiology of renal osteodystrophy. Finally, in collaboration with members of the Cardiology Division we are evaluating the pathophysiology and treatment of left ventricular hypertrophy in patients with chronic kidney disease.


Andrey S. Shaw, MD, professor of pathology and immunology.

 

 

Podocyte Biology and Glomerular Disease

Andrey S. Shaw, MD

Our interest in podocyte biology began with studies of CD2AP knockout mice. These mice leak protein into their urine and then die by six weeks of age. Analysis of renal expression of CD2AP revealed that CD2AP is expressed almost exclusively in the podocyte. Our genetic studies suggest that CD2AP heterozygosity can function together with heterozygosity of other podocyte specific genes to lead to glomerular susceptibility in human patients. This is an exciting result because it is consistent with what we believe is the cause of most common diseases; that multiple small mutations in a wide variety of genes, contribute together to generate susceptibility to chronic kidney failure. We have identified about 2000 podocyte specific genes in humans and have developed efficient, cost-effective methods of sequencing what we hope to be over 1000 patients in the next year. We anticipate that interrogation of these sequences will reveal a large cohort of candidate genes potentially involved in kidney disease. We are currently using mouse genetics to develop a system to test candidate genes in mice. Our system involves the generation of a sensitized ES cell (heterozygous for both CD2AP and synaptopodin), a method for efficient and rapid knock-in of RNAi constructs (into the hgprt locus) and a method of generating pure mice from ES cells. We anticipate that our genetic system will allow us to rapidly screen candidate genes, identified by human sequencing, for their role in the progression of kidney failure.

Disruption of the notochord and floor plate affects the mediolateral positioning of the metanephric mesenchyme (MM).


 




Kendall Blumer, PhD, professor of cell biology and physiology

Piyush Tripathi PhD, postdoctoral fellow

Kalyan Manda PhD, postdoctoral fellow

Cover Illustration: Current Opinion in Organ Transplantation 19(2) 2014 (Hammerman Lab).

 

The BJC Institute of Health opened in 2009. It houses BioMed21.

 

 

RGS 2 and Hypertension

Kendall Blumer, PhD

A long-term goal of our research is to determine how Regulator of G protein Signaling 2 (RGS2) deficiency causes hypertension by dysregulating renal function. This goal is directly relevant to human cardiovascular and renal disease because RGS2 has been shown to be a hypertension quantitative trait locus (QTL) and affect response to antihypertension agents. Although RGS2 deficiency in kidney is sufficient to cause hypertension, it remains unknown which aspects of renal function are dysregulated and how these defects occur. By elucidating these mechanisms, we aim to reveal novel molecular processes that cause renal dysfunction and impact hypertension therapy. We hypothesize that RGS2 deficiency dysregulates G protein-coupled receptor signaling processes that control sodium homeostasis by directly affecting fluid/electrolyte transport and/or renal blood flow. To determine which of these processes are impacted by RGS2 deficiency, we are studying them first in conventional RGS2 knockout mice, and then in nephron-, vascular smooth muscle-, and endothelium-specific RGS2 knockout mice. In parallel we are developing bioluminescence-based imaging reporters that are induced by signaling pathways under the control of RGS2. These reporters will enable us to identify structures in the kidney (e.g. glomeruli, nephron etc.) in which dysregulated signaling occurs because of RGS2 deficiency. This reporter will be used to determine which hypertension therapeutics can correct aberrations in renal signaling caused by RGS2 deficiency.



St. Louis Children's Hospital

Dr. Vikas Dharnidharka directs the Division of Pediatric Nephrology at Washington University and St. Louis Children's Hospital. Drs. Beck and Hmiel, also members of the Division, are interested in calcium metabolism and renal pharmacology respectively.



The Division of Biology and Biomedical Sciences

The Division of Biology and Biomedical Sciences (DBBS) was organized in 1973. DBBS is a graduate educational consortium that includes faculty affiliated with 20 basic science departments in the School of Medicine and the College of Arts and Sciences. DBBS programs are designed to provide a broad interdisciplinary approach to graduate education, emphasizing investigation of important questions in biology. Doctoral programs currently operating within the Division include: developmental biology, evolutionary and population biology, immunology, molecular biophysics, molecular cell biology and biochemistry, molecular genetics, molecular microbiology and microbial pathogenesis, neurosciences and plant biology. DBBS directs one of the largest and most successful Medical Scientist Training Programs offering a combined MD/PhD.



BioMed 21

To any list of momentous dates in the history of life sciences at Washington University, 2003 must now be added as the year in which BioMed 21 was initiated. From the 1909 visit of Abraham Flexner that fueled a redefinition of American medical education through the completion of the Human Genome Project in 2002, few events will have the impact of BioMed 21. It is an intiative that will reshape university culture over the next decade to catalyze and support emerging forms of bioresearch and rapidly convert the knowledge of the genetic blueprint into effective individualized treatments for patients. BioMed 21 is also a building program. Many BioMed 21 activities take place in the BJC Institute of Health, that serves as both a literal and figurative bridge between basic and clinical sciences on the Medical Campus.

Renal Division
Department of Internal Medicine
Washington University School of Medicine