Hanna E. Abboud, MD
O'Brien Research Kidney Center Director
Project 1 & Administrative Core A Principal Investigator
Dr. Abboud is the Jay H Stein Professor and Chief of the Division of Nephrology at UTHSCA. Dr. Abboud received his M.D. degree from the Alexandria University School of Medicine, Egypt, in 1971. His medical internship was at the Johns Hopkins Affiliated Hospitals in Baltimore, MD from 1973 to 1974. This was followed by an internal medicine residency and a clinical nephrology fellowship at the University of Kentucky Medical Center (Lexington) from 1974 to 1976 and 1976 to 1977, respectively. He received research training in renal physiology in the laboratories of Dr. Robin Luke and Theodore A. Kotchen from 1977 to 1978 in the same institution. This was followed by another research fellowship in the Department of Physiology and Biophysics at the Mayo Clinic in Rochester, MN, from 1978 to 1980 in the lab of Dr. Thomas P. Dousa where he studied cell biology and biochemistry. Dr. Abboud was appointed as an Assistant and then tenured Associate Professor of Medicine at Case Western Reserve University School of Medicine. He was recruited to his current position as Professor in the Department of Medicine and Chief of the Division of Nephrology at the UTHSCSA. In 1993 he joined the Center for Molecular Medicine and Institute of Biotechnology (UTHSCSA) as a staff member. He has had sustained funding from the NIIH since 1983, is currently the Principal Investigator on an NIH MERIT Award and is the Center Director of the currently funded O'Brien Kidney Research Center at the UTHSCSA. He is the principal investigator on Project 1 that investigates the genetic determinants of albuminuria. He is also the recipient of Veterans Administration Merit Review awards, and grants from the Juvenile Diabetes Research Foundation and the American Diabetes Association.
Project 1: "Candidate Genes For Albuminuria In Mexican Americans With Diabetes"
Diabetic nephropathy (DN) is the most prevalent cause of end stage renal disease (ESRD) in the United States accounting for approximately 40% of all patients placed on dialysis. Renal failure in diabetic patients leads to accelerated atherosclerosis resulting in greatly increased morbidity and mortality. The growing magnitude of DN and its huge monetary and social costs mandate that we focus on prevention of this disease. New methods are needed to provide early and accurate DN risk estimates. The aims of this project are: To confirm heritability of albuminuria and provide additional evidence of linkage to genetic loci on chromosome 15q and to investigate positional candidate genes(s) influencing susceptibility to albuminuria.
Balakuntalam S. Kasinath, MD
Project 2 Principal Investigator
Dr. Kasinath is a tenured Professor of Medicine in the Division of Nephrology at the UTHSCSA. He is a highly-regarded scientist who runs a well-funded research program. He has maintained sustained extramural funding throughout his career with current funding from the NIH, VA research service, American Diabetes Association and the Juvenile Diabetes Research Foundation. He currently supports research activities of three postdoctoral fellows and a junior faculty. His scientific contributions have been recognized with the Henry Christian Award for excellence of research from the American Federation for Clinical Research in 1994 and invitations to serve on study sections of NIH, VA and the American Diabetes Association. He is also in constant demand to review research proposals from abroad from agencies such as the Medical Research Council of Great Britain, the National Medical Research Council of Singapore, Comitato Telethon Foundazione, Italy, and, Agence Nationale de la Recherché, France. He also serves on the editorial board of Kidney International, the official journal of the International Society of Nephrology. He is frequently invited to deliver lectures at the annual meeting of the American Society of Nephrology and in international meetings. Dr. Kasinath's work over the past seventeen years has focused broadly on understanding the pathogenesis of diabetic kidney disease, with a specific concentration on the metabolism of extracellular matrix.
Project 2: "Insulin Receptor Stimulation in Pathogenesis of Diabetic Nephropathy"
Data obtained from these studies will help elucidate the role of insulin receptor activation in the pathogenesis of diabetic nephropathy. The concept of insulin sensitivity varying among tissues in type 2 diabetes and that insulin receptor can exert a pathologic effect on target tissue damage including the kidney, is novel and is being rigorously tested in this project. Our plans are to generate a kidney proximal tubule epithelial cell specific insulin receptor knock out by strategies described above. We will also further investigate the translational mechanisms involved in regulation of laminin synthesis by renal epithelial and mesangial cells incubated with high glucose and high insulin conditions.
Yumay Chen, PhD
Project 3 Principal Investigator
Dr. Chen is an assistant professor in the department of Medicine in the Division of Nephrology at the UTHSCSA. She is a nationally recognized researcher and has been honored with various awards including the Patricia Welder Robinson Young Investigator Award of the National Kidney Foundation, Outstanding Poster Presentation Award, National Kidney Foundation, and the American Society of Nephrology, Carl W. Gottschalk Research Scholar Award. Her research expertise is in tumor supression, cell cycle regulation, DNA damage response and repair, protein kinase regulation, genetic targeting in mouse. Her laboratory research focus is in: molecular and cellular basis of mitosis during cell division and the pathogenesis of polycystic kidney diseases (PKD). The first part of research will focus on investigating the role of Nek2 in transducing signals in response to genotoxic agents and in regulation by Hec1 of Rad50-mediated DNA repair. A long-term goal is to design agents to prevent or limit chromosome instability due to genotoxic agents in human tumors. The second part of research is involved in exploration of molecular pathogenesis of PKD, especially the involvement of Nek1 protein kinase in Kat and kat2J PKD mouse model. The roles of Nek1 in renal tubular cell proliferation, apoptosis, transcription regulation and DNA damage response and repair will be examined.
Project 3: “Nek1 Protein Kinase and Polycystic Kidney Disease”
The studies proposed, completed, and ongoing will explore unique and potentially unifying molecular mechanisms by which polycystic kidney disease develops and progresses. Once we have clearly understood these mechanisms, we can use the knowledge gained to specifically affect Nek1-dependent pathways, probably by targeted Nek1 over-expression, These studies will also for the first time define functions in higher eukaryotes for Nek1, the first mammalian ortholog of the NIMA (never in mitosis in Aspergillus nidulans), which controls mitotic checkpoints and which is crucial for the survival of lower eukaryotes. The finding that Nek1 is involved in DNA damage repair will allow us to focus some our efforts more directly on where in the DNA damage repair pathway Nek1 works, how Nek1 regulates other proteins known to be crucial to the pathogenesis of PKD, like polycystins, and how inactivation of Nek1 leads to aberrant renal tubular cell apoptosis.
Jeffrey L. Barnes, PhD
Core B Principal Investigator
Jeffrey L Barnes, PhD, is a Professor of Medicine in the Division of Nephrology at the UTHSCSA. Dr. Barnes is an experimental pathologist with a national reputation in the field of renal pathology. He has maintained sustained extramural funding throughout his career with current funding from the NIH and the VA research service. Additional sources of funding over the years include the American Heart Association, the Southern Research Foundation, Abbott Laboratories, Searle Pharmaceuticals, and Probetex, Inc. Dr. Barnes served as Associate Director of the Nephrology Division’s Veterans Administration Research Enhancement Award Program (REAP) and Director or the REAP Morphology Core. He is the Director of the George O’Brien Kidney Center Morphology and Animal Core (2003-2008). He has served on study sections for the VA and the American Heart Association and as an ad hoc reviewer for the NIH and several private granting institutions. Dr. Barnes has served as a referee and panel moderator for the Annual Meeting of the American Society of Nephrology and recently participated in a symposium on Epithelial Mesenchymal Transition at Renal Week 2006. He has served as a Consultant to several Pharmaceutical and Biotechnology companies including Baxter Health Care, Mission Pharmacal, Curagen Corporation, Osprey Pharmaceuticals, Medical Sciences Systems, Inc, and Probetex, Inc. Dr. Barnes’ research has focused broadly on understanding the pathogenesis of kidney disease covering areas of glomerular permeability, role of platelets and mesangial cell behavior in renal disease, and most recently, myofibroblast pathology in renal fibrosis. He has published several manuscripts and reviews on these topics.
Core B: “Transgenic Animal and Morphology Core”
The core provides essential animal and histopathology services required by each investigator in the Center to fulfill the individual specific aims. The Core service provides technical and intellectual assistance in transgenic mouse development and histopathological analysis that are not part of individual investigator laboratories. The core also assures consistency in quality of experimental materials shared by investigators, reduces the numbers of animals, and eliminates need in duplication of effort. The core facility is also used by investigators outside the division and in collaborative work with investigators from other institutions. The plans of the Core are to continue to provide the necessary histopathology and consultation services to address the objectives outlined in the individual projects of the O’Brien Kidney Center and also to provide the same services to outside investigators requiring specialized transgenic animal or morphology techniques.
Pablo E. Pérgola, MD, PhD
Pilot and Feasibility Project Principal Investigator
Dr. Pérgola is an Assistant Professor in the Division of Nephrology, Department of Medicine, at the University of Texas Health Science Center at San Antonio (UTHSCSA), with a joint appointment at the South Texas Veterans Health Care System, Audie L. Murphy Division (STVHCS, ALMD). Since 1990 he has published 19 research papers (10 as first or senior author) in high quality, peer reviewed journals such as the Journal of Applied Physiology, American Journal of Physiology, Circulation Research, and Microvascular Research. His work in vascular physiology and clinical nephrology is funded by grants from the Department of Veterans Affairs and UTHSCSA.
Project: “Antioxidant Treatment in Diabetic Nephropathy”
This project is based on the hypothesis that antioxidants can be used as an adjuvant therapy in the treatment of diabetic nephropathy. The aim is to conduct a randomized, double blind, placebo controlled, crossover study of the effect of the antioxidant N-acetylcysteine (NAC) on the progression of renal disease, blood pressure control, insulin sensitivity and glycemic control, and markers of oxidative stress in patients with type 2 diabetes and overt nephropathy. The PI points out that current therapies, eg, ACE inhibitors (ACEIs) and angiotensin receptor blockers, slow the rate of loss of kidney function in patients with advanced diabetic nephropathy, but do not arrest or reverse the extent of kidney disease in these patients. Thus there is a need to identify additional strategies that might act synergistically with established treatments to produce further retardation or even full arrest of the progression of diabetic kidney disease. Accumulating evidence implicates the generation of reactive oxygen species and increased oxidative stress in the pathogenesis of insulin resistance, impaired insulin secretion, and diabetic complications including nephropathy. Moreover, recent data suggest that antioxidants may slow the progression of renal disease, although data in humans are limited. The primary significance of this project is that it may provide support for the use of antioxidant therapy with NAC as an adjuvant to ACEI in helping to slow the progression of diabetic nephropathy in patients with Type 2 diabetes. Measurements of blood pressure, insulin sensitivity, proteinuria, and markers of oxidative stress may also provide important mechanistic insights into the potential therapeutic effects of NAC.
Jennifer Gooch, PhD
Pilot and Feasibility Project Principal Investigator
Dr. Gooch joined the Division of Nephrology in 1999 shortly after receiving her Ph.D. at the Institute of Biotechnology. Jennifer received her degree in Molecular Medicine from an exceptional program headed by Wen Hwa Lee, Ph.D and Douglas Yee, M.D., Ph.D. During her tenure as a graduate student Dr. Gooch received several awards of recognition including "Outstanding research Award, 1998 and 1st place Cancer Center Council Award for Cancer Research Excellence, 8th Annual Symposium on Cancer Research in San Antonio, 1998. Dr. Gooch has published several papers in high impact journals related to her interest in growth factor-mediated effects in cell signaling and function. Dr. Gooch has worked directly with Dr. Hanna Abboud, Professor and Chief of the Division. She has applied her talents to the renal field where she is now engaged in research investigating the role of calcineurin action in hypertrophy in the diabetic kidney. Dr. Gooch has determined that calcineurin is required for the induction of hypertrophy and extracellular matrix synthesis in cultured mesangial cells and that blockage of calcineurin decreases whole kidney and glomerular hypertrophy and reduces ECM synthesis in type I diabetes.
Project: “Role of Calcineurin in Renal Hypertrophy”
Early diabetic renal hypertrophy is controlled by a variety of hormones, cytokines, and peptide growth factors that, in addition to elevated glucose levels, contribute to the development and maintenance of renal hypertrophy and extracellular matrix accumulation (ECM). However, very little is known about the intracellular signaling pathways utilized by these factors. We have shown that the calcium-dependent phosphatase calcineurin is required for the induction of hypertrophy and ECM synthesis in cultured mesangial cells. In addition, inhibition of calcineurin in a rat model of diabetes decreased hypertrophy of the entire kidney, completely blocked hypertrophy of the glomeruli, and decreased ECM accumulation. However, mechanisms of calcineurin activation are not well-known and targets of calcineurin action in the kidney have yet to be described. Calcineurin is regulated by changes in intracellular calcium and one potential mechanism for cell surface receptor-mediated calcium modulation is generation of reactive oxygen species (ROS) as signaling second messengers. Downstream of calcineurin, the nuclear factor of T cell activations (NFAT) family of transcription factors are targets of calcineurin dephosphorylation and thus may be important for calcineurin action in the kidney. Therefore, calcineurin may be a critical mediator of hypertrophy and ECM accumulation in diabetic renal cells. In addition to calcineurin itself, signaling mechanisms that are required for activation of calcineurin, as well as proteins which are activated downstream of calcineurin, may be successful targets for therapeutic intervention.
Hernan Rincon-Choles, PhD
Pilot and Feasibility Principal Investigator
Dr. Rincon-Choles arrived as a Clinical Fellow in the Department of Medicine, Division of Nephrology at the University of Texas Health Science Center in 1999. He was responsible for the overall coordinating, conducting and supervising of the project's experiments. He played an active role in the development and writing of manuscripts generated from this project.
Project: "Genetics of Diabetic Nephropathy in the Baboon"
Diabetic nephropathy (DN), a microvascular complication of diabetes mellitus (DM), is the main cause of end stage kidney disease worldwide. There is a great need to find animal models of DM and DN that better resemble the physiopathological changes in humans. Both DM and DN are influenced by environmental factors and heredity. The SFBR has approximately 2400 baboons in pedigree colony, with a 10 cM linkage map available for 800 of these animals, and additional animals are being currently genotyped. Some baboons in this colony have developed clinical features of type-2 DM and 4 animals biopsied thus far have histological features similar to those found in humans with DN. In this project we will characterize the phenotype of DN in a subject of animals and investigate the kidney expression of components of the RAS and other cytokines and matrix proteins associated with DN. In this project we will perform a genome-wide search to find and localize quantitative loci that influence variation in albuminuria and disease progression. The goal of this project is to identify early markers of disease progression amenable to intervention.
Nedal H. Arar, PhD
Pilot and Feasibility Project Principal Investigator
Dr. Arar’s research interest focuses on understanding the genetic architecture of complex traits such as albuminuria. Dr. Arar has been working on several projects related to the genetics of nephropathy and diabetes. She has been Co-PI of the Family Investigation of Diabetic Nephropathy (FIND) study, a multi-center genetic study funded by NIH/NIDDK. She has been funded to extend families participated in FIND study by enrolling family members of first, second and third generations. The extended FIND study will permit the addition of extra FIND members that will increase power and allow the applications of different techniques and methods to examine the genetic basis of diabetes and diabetic nephropathy in Mexican Americans. Findings from the FIND study provides evidence in support of chromosomal regions harboring diabetic nephropathy susceptibility alleles on chromosomes 7q, 10p, 14q and 18q, with additional regions linked to albuminuria on 2q, 7q and 15q. The results confirm regions of linkage to diabetic nephropathy on chromosomes 7q, 10p and 18q from prior reports, making it important that genes underlying these peaks be evaluated for their contribution to nephropathy susceptibility (Iyengar, Abboud and Arar et al 2007). The center will provide easy access to large well-established and characterized cohors to replicate such findings. In addition, Dr. Arar performed a genome wide scan/linkage analyses in San Antonio Family Heart Study (SAFHS) and identified a strong linkage peak at chromosome 20q12 (LOD score of 3.5, p = 0.00003) for urinary ACR (Arar et al. 2007). She proposes to replicate these findings using different cohorts in order to search the genome to localize candidate genes that may have functional significance to microalbuminuria. The center will assist Dr. Arar in providing her with phenotypic and DNA samples collected from the San Antonio Family Diabetes Study and with the genetic biostatistics support (core A). The center will provide her with state-of-the art approaches in measuring chronic kidney disease phenotypes such as GFR (core B). Such services are very fundamental more precision in calculating phenotypes relate to CKD to improve our understanding of phenotype-genotype interactions.
Project: “Cultural and ethical issues associated with subjects' participation in genetic family studies”
Several studies showed that there is a genetic basis for the development and progression of diabetic nephropathy (DN) in Non-Mexican American populations (Freedman et al 1993, 1995; Bergman et al 1996; Moczulski et al 1998; Broeckel et al 1998, Krowlewski 1999). 30-40% of Mexican Americans with type 2 diabetes develop nephropathy and ultimately end-stage renal disease (ESRD). Little is known about the clustering and genetics of DN in Mexican Americans. The Family Investigation of Nephropathy of Diabetes (FIND) Study aims to localize genes for DN using concordant and discordant sibpair analytical approach. We are one of 11 Participating Investigation Centers [PICs] (Dr. H. E. Abboud, PI of the San Antonio PIC), enrolling families of Mexican American origin. In this proposal, we will expand our FIND families by enrolling 50 extended, multiplex families in order to search for DN genes with variance components analysis approach. In addition to the genetic study, we will develop and implement a method to enhance subjects’ informed and voluntary participation in genetic family studies. Our current study will complement the FIND study in several ways: (1) enroll and collect data on family members who are currently excluded from the FIND study, which will increase sample size and power related to the FIND linkage analysis, (2) search for DN genes with variance components analysis (VCA), contrarily to the FIND proposed analytical approach (concordant and discordant sibpair). Variance components analysis is considered to be a “semi-parametric” linkage method, because information about the genetic mode of inheritance is not needed. However, strength of VCA is that it estimates the magnitude of genetic effects in addition to the linkage results. Applying a complementary design to the search for DN will enhance our understanding of the genetic basis of complex diseases such as diabetes and DN. Furthermore, enhancing subjects’ informed and voluntary participation will pave the way to place subjects’ protection in practice, especially minority population participating in genetic studies.
Samy Habib, PhD
Pilot and Feasibility Project Principal Investigator
Samy Habib, PhD is Assistant Professor in the Department of Medicine/Division of Nephrology and Research Scientist at the Geriatric Research, Education and Clinical Center, South Texas Veterans Health Care System, Audie L. Murphy Memorial Veterans Hospital, University of Texas Health Science Center, San Antonio, TX. Dr. Habib obtained his PhD in Molecular Carcinogenesis from Roswell Park Cancer Institute, Buffalo, NY. Research in Dr. Habib’s laboratory focused on understanding the role of oxidant stress in the pathogenesis of renal cell carcinoma. His studies explore the role of tuberous sclerosis gene TSC2 in regulating the DNA repair enzyme 8-oxoG-DNA glycosylase (OGG1). He found that deficiency in TSC2 gene that encodes the protein tuberin downregulates the mRNA, protein expression and activity of OGG1 in cultured kidney cells and in tuberin-deficient rat kidneys, heterozygous for the TSC2 gene. He also found that mutations in TSC2 gene in kidney tumors of patients with tuberous sclerosis is associated with several sites mutations in OGG1 gene.
Project: “Role of Diabetes in Development of Renal Cell Carcinoma”
There is an increase in the incidence of cancer including renal cell carcinoma in patients with diabetes. This project deals with the cellular and molecular mechanisms by which hyperglycemia and the enhanced oxygen radicals in diabetes predispose to renal cell carcinoma. This project will: determine if tuberin regulates OGG1 and explore the effect of glucose and oxidative stress on the phosphorylation of tuberin, regulation of OGG1 and production of 8-oxodG in renal proximal tubular epithelial cells from wild type and Eker rats; explore the effect of type I diabetes on the rate of development and severity of renal cell carcinoma in Eker rat model.
Farook Thameem, PhD
Pilot and Feasibility Project Principal Investigator
Dr. Farook Thameem is an Assistant Professor of Medicine, Division of Nephrology at UTHSCSA. His research interests are to identify the genetic factors involved in the development and progression of diabetic nephropathy (DN). Genome-wide linkage analysis identified two major human chromosomal regions; 2q35-37 and 15q12 influencing glomerular filtration rate (GFR) and albuminuria respectively in a Mexican American cohort. Using state of art genotyping technologies such as TaqMan, SNPlex, Illumina golden gate assays and the Baysian Quantitative Trait Nucleotide (BQTN) statistical analytical methods implemented within the program SOLAR (www.sfbr.org/solar).
Project: “Search for Gene(s) Influencing Changes in Glomerular Filtration Rate (GFR) in Mexican Americans”
The objectives and long-term goal of this project are to detect, characterize, and identify gene(s) influencing renal function/failure in diabetes. Our investigation would primarily focus on identifying potential DNA polymorphism(s) in the selected positional candidate genes (IRS1, COL4A3, and COL4A4) that may contribute to the development and/or progression of Diabetic kidney disease. We propose to use high-throughput genotyping methods and novel statistical analyses to precisely define the 2q35-36 linkage region, identify and validate the molecular variant(s) responsible for the decline in GFR in diabetes. An understanding of the role of susceptibility genes and identification of mutations will ultimately allow the development of preventive and therapeutic strategies.
Denis Feliers, PhD
Pilot and Feasibility Project Principal Investigator
Denis Feliers, PhD is Assistant Professor in the Department of Medicine/Division of Nephrology, University of Texas Health Science Center, San Antonio, TX. Dr. Feliers obtained his PhD in Biochemistry from Universite de Paris XI, Orsay, France. Research in Dr. Feliers' laboratory focuses on the regulation of vascular endothelial growth factor (VEGF) synthesis by angiotensin II in renal proximal tubular epithelial cells. He has shown that Ang II, at doses found in the diabetic kidney by micropuncture, stimulates rapid synthesis (within minutes) of VEGF, which was not due to transcription of the vegf gene but rather to increased translation of pre-existing VEGF mRNA, at the level of the 5' untranslated region - 5' UTR (Feliers et al. J Physiol Renal Physiol. 2005 288: F521-9).
Project: "Angiotensin receptors in diabetic nephropathy"
In addition to its direct effects on the kidney, angiotensin II (AII) regulates a variety of mediators of injury in diabetic renal disease. Evidence supports a role for vascular endothelial growth factor (VEGF) in diabetic nephropathy. Our data show that AII promotes rapid synthesis of VEGF in proximal tubular epithelial cells by stimulating mRNA translation. Our objective is to study the role of AII and its receptors in regulation of mRNA translation of VEGF and matrix proteins in diabetic renal disease. Our hypothesis is that high glucose recruits AII which binds to AT1 receptor (AT1R) and AT2 receptor (AT2R) to increase mRNA translation and synthesis of VEGF and matrix proteins in proximal tubular epithelial cells in diabetes, leading to kidney hypertrophy, changes in glomerular filtration rate (GFR) and albuminuria. The specific aims of this project are (1) to study the role of AII receptors in the diabetic kidneys. Mice with type 1 diabetes will be studied on 1 day and at 2 months of disease. VEGF mRNA translation will be assessed by polysome assay. Cap-dependent translation will be studied by 4E-BP1 phosphorylation and formation of eIF4E/eIF4G complexes. Activation of hnRNPK and binding to mRNAs will be monitored. Matrix expansion will be monitored by expression of fibronectin and type IV collagen. These parameters will be correlated with kidney hypertrophy, albuminuria and changes in GFR. AT1R and AT2R blockers will be employed to assess the role of AII in these processes and (2) to determine the role of AII receptors in VEGF and matrix protein synthesis in renal cells. Mouse proximal tubule epithelial (PTE) cells, that form the bulk of renal cortex, will be exposed to 30 mM glucose (HG) with appropriate controls, and VEGF expression will be measured. AT1R and AT2R blockers will be used to determine role of AII in HG regulation of VEGF synthesis. Increase in matrix synthesis will be studied by examining expression of fibronectin and collagen IV. Cap-dependent mRNA translation will be studied as described in Specific Aim 1. Involvement of hnRNPK in regulation of VEGF synthesis, cell hypertrophy and matrix expansion by HG will be studied using specific small interfering RNA. Data obtained from these studies are likely to unravel unique roles for AII receptors in regulation of events that regulate mRNA translation in the diabetic kidney.
Yves Gorin, PhD
Pilot and Feasibility Project Principal Investigator
Dr. Yves Gorin is an Assistant Professor in the Department of Medicine/Division of Nephrology at the University of Texas Health Science Center at San Antonio (UTHSCSA). Dr. Gorin received his Ph.D. at the University of Paris XI, France, where he had extensive training in the field of reactive oxygen species biochemistry. Dr. Gorin's research has been dedicated to elucidating the regulatory mechanisms of NAD(P)H oxidases of the Nox family for years. Initially, he contributed to the identification and purification of the thyroid NAD(P)H oxidase, a member of the Nox family, now referred to as Duox, that is implicated in the thyroid hormone biosynthesis.
Since coming to the United States, Dr. Gorin has been associated with the Division of Nephrology at the UTHSCSA, and his research focuses on the role of oxidative stress in kidney disease with emphasis on diabetic nephropathy. His studies demonstrated that reactive oxygen species generated by the NAD(P)H oxidase homologue Nox4 mediates the hypertrophic and fibrotic response to the vasoactive peptide angiotensin II in kidney cells, which play an important role in kidney fibrosis (Gorin et al., Am J Physiol Renal Physiol, 2003). Activation of the renin-angiotensin contributes to the development and progression of kidney diseases including glomerulonephritis and diabetes. Dr. Gorin's laboratory also demonstrated that Akt and ERK kinases signaling cascades are downstream targets of Nox4-derived reactive oxygen species in the pathway linking angiotensin II to hypertophy and fibrosis (Gorin et al., FASEB J, 2001; Gorin et al., Am J Physiol Renal Physiol, 2003; Gorin et al., Biochem J, 2004; Block et al., Antioxidant Redox Signal, 2006). These results have significant clinical implications in the understanding and prevention of renal fibrosis and the development of end-stage renal disease.
The search for the role of Nox enzymes in the pathogenesis of diabetic nephropathy has culminated with the identification of NAD(P)H oxidase Nox4 as mediator of renal hypertrophy and glomerular fibrosis in a rat model of type 1 diabetes. Dr. Gorin's research group was among the first to show the critical role of Nox4 in early manifestations of diabetic nephropathy. His research performed in an experimental model where diabetic animals are treated with antisense oligonucleotides directed against Nox4, suggests that inhibition of the oxidase activity significantly improved renal disease (Gorin et al., J Biol Chem, 2005). These results are significant in understanding the mechanisms of diabetic kidney disease and in designing strategies to prevent the progression to end-stage renal failure. Dr. Gorin's Juvenile Diabetes Research Foundation and National Kidney Foundation awards examine the involvement of Nox4 oxidase in the manifestations of advanced diabetic nephropathy such as proteinuria and sclerosis by performing long-term.
Project: "Nitric Oxide, NAD(P)H oxidases and Diabetic Nephropathy"
Oxidative stress has been implicated in the pathogenesis of diabetic nephropathy (DN). We have evidence that endothelial nitric oxide synthase (eNOS) is present in cultured glomerular mesangial cells (MCs) and that the enzyme generates reactive oxygen species (ROS) rather than nitric oxide upon stimulation with angiotensin II (Ang II) or high glucose concentration (HG), phenomenon referred to "uncoupling". In addition, Ang II and HG mediate hypertrophy and fibronectin expression in MCs through generation of ROS via the NAD(P)H oxidase Nox4. We demonstrate that NADPH-dependent ROS generation is increased in the kidney of rats with streptozotocin-induced diabetes and that inhibition of Nox4 using an antisense oligonucleotide therapy reduces diabetes-induced renal ROS generation, hypertrophy and fibronectin expression. The study will identify important mechanisms involved in renal pathology, and help establish effective therapeutic modalities for treatment of DN.
Brent Wagner, MD
Pilot and Feasibility Project Principal Investigator
Brent Wagner, M.D., is a graduate of the University of New Mexico School of Medicine (1999). He has a master’s degree (M.S.) in Biomedical Sciences from UNM (1995). His thesis was based on the transport of cyanide-containing glucogenic compounds in the small intestine and the utility of compartment modeling applied to transport kinetics (Wagner B and Galey WJ, J Appl Toxicol 23(2003)371). He underwent the American Board of Internal Medicine Research Investigator Pathway for his Internal Medicine residency and Nephrology fellowship at the University of Texas Health Science Center at San Antonio. He was supported via National Kidney Foundation two-year research fellowship and the Jack C. Kent third year research fellowship awards. During this time, he published a peer-reviewed case report on statin-induced myopathy (Wagner B et al. Journal of Musculoskeletal Pain 11(2003)25), while conducting research on kidney development. He is now a certified specialist in Internal Medicine and Nephrology and currently the Associate Program Director of the nephrology training program. Dr. Wagner’s research focuses on the roles of the platelet-derived growth factor receptor and reactive oxygen species in renal organogenesis, specifically the NADPH oxidase (Nox) homolog 4. Since joining the Division of Nephrology in 2001, his lab has isolated and cultured metanephric mesenchymal and ureteric bud cells from embryonic mouse kidney. He is currently funded by a 5-year American Heart Association Fellow-to-Faculty Transition Award on the study of the signal transduction pathways mediated by the PDGF receptor β and Nox4 in nephrogenesis. He is currently characterizing the spatial and temporal expression of the PDGF receptor β, Nox4, and the mechanisms by which the latter mediates DNA synthesis (Wagner et al. Journal of the American Society of Nephrology 18(2007)2903) and migration in embyronic perivascular renal cells. His colleague, Goutam Ghosh Choudhury, recently demonstrated an interaction between the PDGF receptor β and the phosphatase and tensin homolog (PTEN) in adult mesangial cells (Journal of Biological Chemistry 279(2004)15258). His interests include how PDGF signaling is terminated by PTEN in the developing kidney.
Project: “Nox Oxidases and Mesangial Cell Development”
The overall objective of this proposal is to elucidate the role of NAD(P)H oxidase homologs (Nox) in the development of mesangial cells (MCs), with specific attention to their position in signal transduction pathways activated by the platelet-derived growth factor (PDGF) B chain. It is our hypothesis that the developmental regulation of the NAD(P)H oxidase homolog, Nox4, is PDGF receptor (PDGFR) β-dependent during critical periods of nephrogenesis. Moreover, it is the hypothesis of the applicant that Nox4 transduces signal transduction pathways activated by PDGFRβ to regulate migration and proliferation of MMCs and their differentiation to MCs.