Division of Nephrology-Hypertension

Research Overview

The Division of Nephrology-Hypertension at the University of California San Diego and Veterans Affairs San Diego Healthcare System offers multiple and diverse research activities which include clinical, translational and basic science studies. The Nephrology-Hypertension faculty are well funded with total annual funding in excess of $10 million, including NIH, VA, corporate and foundation sources.

The division holds two major NIH training grants in Hypertension and Clinical Investigation in Nephrology and obtains training awards each year from various foundations and corporate entities.

Dr. Ravi Mehta is the PI on a large K30 NIH award, which funds educational efforts to train faculty and fellows in clinical and translational research including biostatistics, epidemiology and outcomes research. Dr. Carolyn Kelly is the co-principal investigator on the pre-doctoral training component of the UC San Diego CTSA. This training grant supports training in clinical research for pre-doctoral students in the Schools of Medicine and Pharmacy at UC San Diego.

Major Areas of Research

Hypertension

The Ziegler lab studies the regulation of blood pressure, particularly by the autonomic nervous system. There is a focus on hypotensive disorders including autonomic neuropathies, POTS and the postural hypotension astronauts experience on return to earth's gravity. Hypertensive disorders under study include PTSD, sleep apnea and chronic stress responses. The lab develops non-invasive tools to study the baroreflex, chemoreflex pulse transit time, flow mediated dilation and heart rate variability. These tools measure cardiovascular responses to interventions such as Tai Chi or behavioral activation counseling to evaluate if they decrease pressor responses and promote vascular health.

Dr Robert Parmer’s research includes both laboratory-based basic research and patient-oriented clinical investigation, and focuses on studies to better understand the pathophysiologic mechanisms underlying blood pressure regulation and hypertension. Clinical studies focus on autonomic and renal mechanisms of blood pressure regulation, including studies of sympathoadrenal and renal serine protease activity, sodium homeostasis, and renal hemodynamics in hypertension. Basic studies focus on the role of the plasminogen activation system in catecholaminergic/sympathoadrenal function and renal function. Recent studies have included the identification of a novel protein, Plg-RKT, an integral transmembrane protein that serves as a major plasminogen receptor on various cell types and tissues, and which markedly accelerates activation of plasminogen to the active protease plasmin.

The Vaingankar lab uses a functional genomics approach to study genes involved in the pathophysiology of the complex human traits of hypertension and kidney disease. In particular they study the involvement of the granin family of genes in regulating blood pressure and look for genetic associations with cardiovascular and kidney disease. They create haplotypic variant mouse models and unambiguously test human gene polymorphisms in vivo. The lab also profiles biomarkers in acute kidney injury- proteomic, epigenomic modifications and non-coding RNAs to understand how gene expression is regulated in kidney injury and is predictive in the development of disease.

Dr. Sushil Mahata’s Metabolic Physiology and Ultrastructural Research Laboratory investigates the role of Chromogranin A and its peptides Catestatin and Pancreastatin in regulation of hypertension, diabetes, insulin resistance, obesity, and substrate metabolism in knockout, genetically obese, and diet-induced obese mice. They also investigate the therapeutic effects of Catestatin and Pancreastatin variants/mimetics in alleviation of the above disorders. Recent studies focus on the ultrastructural and functional regulation of mitochondria during endurance exercise with special reference to mitochondrial dynamics (mitochondrial fission and fusion), cristae architecture and high-resolution respirometry in chromaffin cells, cardiomyocytes, hepatocytes, and adipocytes.

Dr Dena Rifkin studies issues related to kidney disease, blood pressure, and aging. She is funded to study 24-hour blood pressure patterns and highlights of her work include: a pilot VA clinical trial of home blood pressure monitoring, a VA investigation of coronary calcium in dialysis patients, a locally recruited study of associations in community-living elders between 24-hour blood pressure and cognition and between 24-hour blood pressure and kidney function. Current fellows are examining issues of depression and CKD, and patients' understanding of renal prognosis.

 

Kidney Physiology and Pathophysiology

Dr. Scott Thomson’s investigations focus upon the coordination of tubular and glomerular function primarily via the tubuloglomerular feedback system. Inaddition, there are multiple studies on the hormonal control of tubular and glomerular function, focusing upon angiotensin II, nitric oxide synthaseisoforms, adenosine, and purinergic receptors. Studies using rat micropuncture examine the roles of a variety of ion channels, insulin and other factors that regulate tubular function.

The Vallon lab studies the physiology, pathophysiology and pharmacotherapy of the kidney and cardiovascular system, and offers new insights into the molecular determinants and regulation of renal transport processes, blood pressure, the diabetic kidney and mechanisms of acute and chronic kidney disease. The group makes use of gene-targeted mouse models to dissect contributions of specific genes/proteins to address clinically relevant questions. The Vallon lab is one of few that performs in vivo renal micropuncture at the single nephron level of the rat and mouse. They developed the tubular hypothesis of glomerular filtration and nephropathy of the diabetic kidney, a concept that puts tubular growth and hyper-reabsorption at the center of the early pathophysiology of the diabetic kidney.

Dr. Prabhleen (Sheena) Singh’s laboratory examines the key renal hemodynamic and metabolic adaptations at the onset of acute and chronic kidney injury. Her research focuses on the coupling of tubular transport and metabolism and novel regulators of these processes such as HIF-1a and AMPK in clinically relevant models of AKI and CKD. She utilizes physiological techniques to measure in-vivorenal hemodynamics, renal micropuncture to assess glomerular and tubular function at a single nephron and whole kidney level, in-vivo and ex-vivo kidney oxygenation and mitochondrial bioenergetics. Current projects include assessment of intrarenal hemodynamics along with determinants of oxygen utilization and mitochondrial function in models of AKI include ischemia reperfusion, cecal ligation and puncture models of sepsis and models of diabetic and non-diabetic CKD.

Dr. Timo Rieg’s laboratory studies various aspects of kidney function and blood pressure regulation under physiological and pathophysiological conditions. His laboratory is specifically interested in specific roles of ion channels, transporters, receptors and intracellular signaling pathways in the biology of the kidney and intestine. Their research aims to provide new insights into electrolyte transport, glomerular function, and the role of the kidney as well as the intestine in the regulation of electrolyte homeostasis and blood pressure. Their group uses in vivo (e.g. blood pressure and GFR in awake mice) and in vitro approaches to dissect the contribution of specific genes by using disease relevant animal models.

Kidney Development

Dr. Sanjay Nigam studies the molecular mechanisms, which underlie kidney development with a specific interest in kidney organogenesis and tissue engineering. Other studies focus upon the biology and significance of "drug" transporters with a particular interest in the SLC22 family of transporters. Among these are the organic anion transporters (OATs) and organic cation transporters (OCTs) as well as other interesting SLC22 transporters--including a number discovered in the lab. These transporters are involved in the handling of many small molecule drugs, toxins and metabolites in the kidney and other organs. Their group employs in vitro, ex vivo, in vivo (knockout) and computational methods.

Kidney Immunopathogenesis and Transplantation Immunology

Dr. Dianne McKay’s laboratory has had a long-standing focus on the immunologic mechanisms of ischemia-induced tissue injury with a particular interest in the innate immune system in renal ischemia/reperfusion injury (IRI). Work from her laboratory has shown that renal tubular cells release immunologically active molecules (danger activated molecular pattern molecules – DAMPs) after ischemic injury and demonstrated that receptors for the released DAMPs (called pattern recognition receptors – PRRs) are constitutively expressed on renal tubular epithelial cells. The lab has also discovered that expression of some of these receptors is regulated following brief periods of hypoxia and that blockade of specific PRRs is highly protective from experimental renal IRI. Another focus is on the role of PRR signaling in hematopoietic stem cell (HSC) engraftment in models of alloantigen-induced tolerance. The laboratory has recently demonstrated that specific TLRs and NLRs are expressed on HSCs and that these receptors play a critical role in HSC engraftment in bone marrow transplant models. The work in Dr. McKay’s laboratory is focused now on understanding the mechanisms by which modulation of TLR and NLR signaling influences responses to ischemic injury in both renal IRI models and in bone marrow transplant models. The data obtained from ongoing experiments in Dr. McKay’s laboratory will extend our understanding of the innate immune system as a key initiator of tissue injury in renal IRI and will provide new knowledge applicable to targeted therapies for enhancing the viability and engraftment of HSCs for allogeneic transplantation.

Diabetic Nephropathy

Dr. Kumar Sharma has taken a translational approach in studying diabetic complications and has expertise in developing phenotype analysis using imaging, molecular and biochemical methods, genomics, microarray and proteomics. His studies have employed imaging and systems biology approaches to understand novel mechanisms related to obesity-related complications, diabetic kidney disease and innovative therapies. His current focus has been development of novel biomarkers for chronic kidney disease and diabetic complications. In particular, recent metabolomic and mitochondrial studies in animal models and humans have led to novel insights and new theories into the pathogenesis of diabetic complications and the role of the kidney in energy metabolism.

Acute Kidney Injury

Dr. Ravi Mehta and Dr. Dinna Cruz research outcomes in the ICU setting with an emphasis on acute kidney injury (AKI). The University of Alabama-UCSD O'Brien Center for Acute Kidney Injury (AKI) Research Center is a George M. O'Brien Kidney Research Center supported by a P30 grant from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the University of Alabama at Birmingham School of Medicine, the Division of Nephrology and the University of California, San Diego School of Medicine and Division of Nephrology. Our center supports shared core facilities to enhance collaborations and further research understanding, and fosters interactions among investigators from different backgrounds and disciplines who share an interest in kidney research. The O’Brien Center also provide intellectual resources and infrastructure to attract new and established investigators to AKI research.

Bone Mineral Disorders

Dr. Joachim Ix’s research focuses on novel therapies for chronic kidney disease mineral bone disorders (CKD-MBD). His team has used large observational studies to quantify the strength of associations of CKD-MBD with cardiovascular disease and related outcomes in CKD patients. The strength and consistency of these findings makes intervention to improve CKD-MBD an important target in lowering cardiovascular disease event risk in CKD patients. He has identified novel therapies that lower intestinal phosphate absorption, and is evaluating safety and efficacy of these therapies in CKD patients in multi-center randomized clinical trials. His team is also interested in identifying novel non-invasive markers of kidney tubule cell health. Dr. Ix’s team has evaluated blood and urine proteins that assess the health of kidney tubule cells, and are working to determine if these markers improve assessment of risk of future kidney disease progression and cardiovascular disease risk.