The 2015-2016 Pilot Project award recipients are Dewan S. A. Majid, MBBS, PhD; Hongbing Liu, PhD; and M-Altaf Khan, PhD
Dewan S. A. Majid, MBBS, PhD
Professor,
Department of Physiology
Phone: (504) 988-2588
Room #: 4020
Email: majid@tulane.edu
Roles of TNF-α receptors in high salt induced exaggerated hypertensive & renal injury responses to Angiotensin II
Dr. Majid completed his PhD in 1989 from the University of Leeds in England, and his MBBS (Bachelor of Medicine & Bachelor of Surgery) in 1978 from Chittagong University in Bangladesh. After completing his postdoctoral training in the Department of Physiology at Tulane University, he was appointed to the faculty in 1992, raising through the rank to Professor in 2007.
PILOT PROJECT RESEARCH: Although high salt (HS) intake alone induces minimal changes in blood pressure, it exaggerates the hypertensive and renal injury (RI) responses to elevated angiotensin II (AngII) levels. The mechanisms for such exaggerated responses remained unresolved. Tumor necrosis factor-alpha (TNF-a), a pro-inflammatory cytokine that is stimulated by AngII and HS intake, has been implicated in AngII induced salt sensitive hypertension (SSH); however, its’ mechanistic role in SSH and RI is not yet clearly defined. TNF-α exerts its biological responses via interaction with two cell surface receptors, TNFR1 and TNFR2 which are differentially expressed and regulated in the kidney. In this proposed study, Dr. Majid will test the hypothesis that ‘the exaggerated hypertensive and renal injury responses to elevated AngII levels during HS intake are due to a reduction in TNFR1 activity and increases in TNFR2 activity, causing decreases in proxynitrite (ONOO-) formation and in interleukin-10 (IL-10) activity in the kidney which collectively a) minimize TNF-α induced natriuretic responses leading to further increase in salt retention and b) exacerbate pro-inflammatory responses leading to enhanced renal tissue injury’. A vertically integrated approach involving in-vivo studies using mice & rats will be employed to evaluate the interactive roles of TNF-a, ONOO- and IL-10 in mediating hypertensive and renal injury responses to chronic AngII+HS intake. Acute renal studies include standard clearance and hemodynamic studies while in chronic experiments, systemic blood pressure will be assessed using radio-telemetry. Direct measurement of renal tissue OONO- concentrations using electron paramagnetic resonance (EPR) with estimation of inflammatory cytokines in the renal tissues using ELISA measures will be performed. Using this integrated approach, Dr. Majid anticipate that he would be able to identify definitive roles for TNF-a receptors in regulating renal tissue levels of OONO- and IL-10 in the pathophysiology of SSH and associated renal injury induced by chronic AngII and HS treatments that may lead to the development of effective therapy for this clinical condition.
RELEVANCE: Understanding the interactive role of AngII, ONOO- as well as inflammatory cytokines in SSH and RI may determine the level of salt sensitivity in any subject or groups of individuals and thus, the findings in this investigation may clarify the reason for the heterogeneity in the blood pressure response to HS intake in the general population. Such information is essential to the primary prevention of SSH and RI in humans.
Hongbing Liu, PhD
Assistant Professor,
Division of Pediatrics Nephrology,
Department of Pediatrics & Department of Biochemistry,
Phone: (504) 988-6244
Room #: 5517
Email: hliu8@tulane.edu
Histone Deacetylases 1 and 2 in Kidney Development
Dr. Liu completed his PhD in 2003 from Hong Kong polytechnic University in Hong Kong. His Postdoctoral trainings in both Developmental Biology & Developmental Genetics were completed from Tulane University and in 2014, Dr. Liu was appointed Assistant Professor to the Division of Pediatrics Nephrology, in the Department of Pediatrics & the Department of Biochemistry and Molecular Biology, at Tulane University.
PILOT PROJECT RESEARCH: Congenital Anomalies of the Kidney and Urinary Tract (CAKUT) are a major cause of morbidity in children, constituting approximately 20~30% of all anomalies identified in the prenatal period. CAKUT plays a causative role in 30~50% of cases of end stage renal disease (ESRD) in children, and predisposes to the development of hypertension and other renal-cardiovascular diseases in patients that survive to adolescence and adulthood. Therefore, CAKUT poses a significant economic burden on health care systems related to the patients' lifelong costly therapeutic needs. The long-term goal of our study is to uncover the epigenetic mechanisms accounting for CAKUT. Dr. Liu proposes to investigate the nephric lineage-specific functions of class I histone deacetylases (HDACs), HDAC1 and HDAC2, in kidney development. HDACs are an evolutionarily conserved group of enzymes that remove acetyl groups from histones as well as non-histone proteins. His preliminary data indicate that HDAC1 and HDAC2 play redundant yet essential functions in the renal progenitor cells: double deletion of HDAC 1 and HDAC2 in the renal progenitor cells disrupts nephron formation, due to defective cell proliferation and differentiation. Dr. Liu also found the double deletion resulted in ectopic expression of Wnt4, which indicates that HDAC1/2 prevents premature differentiation of cap mesenchyme cells through inhibition of Wnt/ β-catenin target genes, including Wnt4. Therefore, he hypothesizes that HDAC1 and 2 in the renal progenitor cells are required to maintain nephron progenitors during kidney organogenesis. Two specific aims are proposed to test this hypothesis: (1) To determine the role of HDAC1 and 2 in the regulation of Six2 expression in nephron progenitors; and (2) To determine the role of HDAC1 and 2 in the balance of self-renewal and differentiation of renal progenitor cells. The results will provide new insights into the epigenetics of kidney development and will open new avenues to novel strategies for the prevention and treatment of CAKUT and its associated renal-cardiovascular diseases, through pharmaceutical agents that target epigenetic modifiers. Such epigenetic drugs are already in clinical use or under investigation for the treatment of cancer as well as other.
RELEVANCE: The word “epigenetics” literally means “on top of or in addition to genetics.” It is defined as the mechanisms that initiate and maintain heritable patterns of gene expression without changing the DNA sequence. This is particularly significant because there is increasing evidence that epigenetic mechanisms play a critical role in the development of a number of human diseases, such as, neurodevelopmental disorders, cardiovascular diseases, type-2 diabetes, obesity and infertility.
M-Altaf Khan, MSCR, PhD
Assistant Professor,
Section of Nephrology & Hypertension,
Department of Medicine
Phone: (504) 988-1361
Room #: 7518
Email: akhan2@tulane.edu
Roles of TLRs and ROS in contrast-induced nephropathy and new therapeutic strategies
Dr. Khan completed his PhD in 1998 from the University of Arkansas. He then completed his Postdoctoral training in Molecular Biomarkers from Louisiana State University, in Genomics from Mississippi State University, and in Nephrology Research from Tulane University. In 2013 he was appointed to faculty to the Department of Medicine, Section of Nephrology & Hypertension, at Tulane University.
PILOT PROJECT RESEARCH: Radio-contrast media (CM) are commonly used to enhance imaging in diagnostic procedures. Every year, almost 8 million patients admitted to emergency departments with acute chest pain undergo critical diagnostic imaging using CM. Importantly, CM can cause significant renal injury, known as contrast-induced nephropathy (CIN) and patients with renal impairment, diabetes, hypertension and cardiac disorders have the highest risk of developing CIN. An effective preventive strategy for CIN is not available due to incomplete understanding of the disease mechanism, lack of a reproducible animal model that mimics human CIN, and unidentified CIN-specific drug targets. In this study, Dr. Khan will investigate the pathophysiology of CIN in elderly diabetic and hypertensive (eNOS-deficient) mice and develop novel therapeutics to prevent CIN. Recent research demonstrated that reactive oxygen species (ROS) and innate immunity mediated through Toll-like receptors (TLRs) are major contributors to CIN pathogenesis. However, their integrated causal roles in CIN have not been investigated. The overall objective is to determine the role of ROS and TLRs in CIN, identify new drug targets, and to evaluate the antioxidant and anti-inflammatory responses of rosuvastatin and sodium bicarbonate on CIN amelioration. The following specific aims are proposed: 1) Develop a diabetic CIN mouse model using CM iohexol in endothelial nitric oxide synthase (eNOS) deficient mice. 2) Determine the role of TLRs, ROS and renin-angiotensin system in the pathogenesis of CIN. 3) Evaluate the therapeutic effects of rosuvastatin and sodium bicarbonate to ameliorate CIN. The expected outcome will provide a base for further in-depth studies and have an important impact on the prevention of CIN especially in patients with diabetes and cardiovascular disorders and will promote the Renal COBRE mission to provide safer radio-imaging procedures. The long-term goal is to develop a reliable preventive strategy against CIN and move forward these newly identified therapeutics into clinical studies.
RELEVANCE: This study will explore mechanisms of kidney injury due to diagnostic contrast dye and will also facilitate more rapid functional recovery of the injured kidney. Successful outcome should facilitate the development of new therapeutic drugs against contrast-induced renal injury and allow safer radio-contrast enhanced diagnostic imaging procedures for patients in community especially in elderly with diabetics.
