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Department of Medicine

Department of Medicine

  Division of Renal-Electrolyte

RESEARCH


 

Epithelial Cell Biology and Physiology

Gerard Apodaca
Catherine Baty
Cary Boyd
Marcelo Carattino
Rebecca Hughey
Edwin Jackson
Ossama Kashlan
Thomas Kleyman
Evan Ray
Ankita Roy
Arohan Subramanya
Ora Weisz

 

Acute Kidney Injury

Mohammad Al-Bataineh
Becky Hughey
Rod Tan

 

Kidney Fibrosis

Roderick Tan

 

Lower Urinary Tract

Gerard Apodaca
Lori Birder
Marcelo Carattino
Youko Ikeda
Aura Kullman
Steven Truschel

 

Hypertension

Cary Boyd
Edwin Jackson
Ossama Kashlan
Thomas Kleyman
Evan Ray
Ankita Roy
Arohan Subramanya

 

Transplantation Immunology

Geetha Chalasani
William Hoffman
Fadi Lakkis
David Rothstein

 

Clinical Studies in Nephrology and Transplantation

Filitsa Bender
Linda Fried
Sundaram Hariharan
John Hotchkiss
Manisha Jhamb
James Johnston
Kelly Liang
Rajil Mehta
Beth Piraino
Chethan Puttarajappa
Helbert Rondon
Jane Schell
Nirav Shah
Puneet Sood
Steven Weisbord
Christine Wu

 

 

Basic Science

 

Al-Bataineh, Mohammad


My current research focuses primarily on studying the acute and chronic effects of the cell surface protein mucin 1 (Muc1) in regulating the b-catenin pathway during moderate and severe ischemia-reperfusion injury (IRI) in a mouse model.

   

 

Apodaca, Gerry


Apodaca Lab

My lab studies the biology of the epithelial cells that line the inner surface of the bladder and ureters (urothelium), as well the cells that line the tubules that comprise the kidney nephron. We have three major projects in the laboratory:

1. Studies of stretch-regulated membrane traffic in umbrella cells

2. Analysis of tight junction morphology and function in response to stretch

3. Exploration of what the role is of uroplakins in urinary tract development and congenital anaomalies of the kidney and urinary tract

   

Baty, Catherine

Dr. Baty's research interests are on the role of lymphatic vasculature in health and disease. She collaborated with geneticists Robert Ferrell and David Finegold to first identify connexin mutations as a cause of lymphedema in humans. She is an expert live cell microscopist and has developed a variety of functional assays of lymphatic endothelial cells to test lymphedema mutations in vitro. With her recent move into the Renal-Electrolyte Division she has begun to investigate the role of renal lymphatics as well as develop other live cell physiologic techniques including ex vivo kidney slice cultures and isolation and perfusion of renal proximal tubules.

   

Birder, Lori

My laboratory is interested in understanding the complexities of urinary bladder epithelial (urothelial) cell function and urothelial cell-neuronal interactions. Our investigations have revealed that the urothelium, a stratified epithelial layer that lines the bladder lumen, might have the capacity to send signals to neighboring cells via the release of chemical mediators. Our identification of a number of functional receptors/ion channels in bladder urothelial cells and the possible involvement of these receptors/ion channels in the release of mediators suggest that these cells exhibit specialized sensory and signaling properties. This arrangement would represent a departure from the conventional view of the urothelium as a simple barrier and provide further support for our speculation that the urothelium has "neuron-like" properties and that it may play a role in sensory mechanisms in the urinary bladder. Through an array of experimental approaches that include molecular biology (mouse knockouts; qRT-PCR, western blot; quantitative morphology), functional assays (measurement of transmitters; mitochondrial function; Ca2+/confocal imaging; in vivo assessment of bladder function and pain behavior), our goals are to further characterize the properties of urothelial cells. Elucidation of mechanisms impacting on urothelial function in addition to how pathology may impact on mechanisms of urothelial communication may provide important insight into targets for new therapies for the clinical management of lower urinary tract disorders.

   

 

Carattino, Marcelo

Dr. Carattino's main research interests are epithelial ion transport, and regulation of ion channels by mechanical forces. He is also studying how proteolytic processing of the epithelial sodium channel regulates its activity. His main tools involved electrophysiological techniques, as single channel recording, two-electrode voltage clamp, short circuit currents of epithelial cell monolayers, and molecular biology techniques.

   

 

Chalasani, Geetha

Dr. Chalasani's main interests in transplantation immunology are memory T cell biology and pathogenesis of chronic rejection. Her laboratory is focused on understanding how memory T cells are generated in transplantation. She is investigating B cell-Tcell interaction in promoting T cell memory. Another area of research in her laboratory is understanding the role of innate immune activation in the pathogenesis of chronic rejection.

   

Hughey, Rebecca

Research in my laboratory is focused on characterization of the assembly, processing and membrane trafficking of apically expressed glycoproteins in polarized kidney epithelial cells. We use biochemistry and electrophysiology techniques in cultured cells and Xenopus oocytes, as well as transgenic mice, to study the function of glycosylation, palmitoylation and proteolytic processing of model proteins such as the epithelial sodium channel (ENaC), gamma-glutamyltranspeptidase and the cell surface sensor MUC1. Our recent studies have revealed that ENaC is activated by a very novel mechanism of proteolytic release of inhibitory peptides both in the biosynthetic pathway and post-Golgi compartments, and in pathological states such as proteinuria (kidney) and Cystic Fibrosis (lung). Our current studies of MUC1 function in normal kidney epithelia are focused on its role in epithelial survival and recovery from acute kidney injury using both a model of polarized kidney epithelial cells cultured under hypoxic conditions, and a proven mouse model of kidney ischemia-reperfusion injury.

   

Ikeda, Youko

It has been demonstrated that there are multiple intercellular signaling mechanisms that occur within the urinary bladder wall to modulate sensory outflow and thus affect storage and voiding function.  Alterations in bladder sensory function have been attributed to a number of pathologies including, interstitial cystitis, and overactive and underactive bladder syndromes. There is limited number of therapeutic options for these conditions and further understanding of bladder sensory regulation is necessary to elucidate new treatment modalities.

Our lab has demonstrated communication of urothelial cells with lamina propria pacemaker interstitial cell.  In certain pathologies, bladder interstitial cells become interconnected by gap junctions. This permits interactions with the detrusor smooth muscle to enhance autonomous bladder contractions and stimulation sensory nerves responsible for initiating micturition; therefore contributing to overactive bladder symptoms.  Our research has now expanded to also examine the interaction of sensory nerves with interstitial cells and the bidirectional communication between sensory neurons and the urothelium.

The overall goal of our research is to characterize the intrinsic communication mechanisms between the different layers of the bladder wall and determine their role in lower urinary tract dysfunction.

   

Kanai, Anthony

Treatment/Mechanisms of Lower Urinary Tract Dysfunction Following Spinal Cord Injury
1)Investigate neural remodeling in the urinary bladder or spinal cord using viral constructs, optogenetics and novel imaging approaches including dual-camera selective plane illumination confocal microscopy.
2) Determine the efficacy of novel small molecule inhibitors (synthesized in house) of the p75 neurotrophin receptor responsible for urothelial and neuronal cell apoptosis following spinal cord injury.
3) Characterize the therapeutic benefits of new approaches in arresting bladder overactivity including botulinum neurotoxin Type-A, ?3-adrenergic receptor agonists or proNGF/proBDNF antibodies.PDE5 Inhibition of Afferents and Interstitial Cells in Overactive Mouse Bladders
4) Determine the acute and chronic effects of PDE5 inhibition on bladder sensory nerve and interstitial cell activity in acrolein-induced chemical cystitis.
5) Characterize the mechanism by which long-term PDE5 inhibition overcomes fibrosis and increases urinary bladder contractility. 
6) Investigate the therapeutic benefits of stimulators and activators of soluble guanylate cyclase as an alternative approach to the use of PDE5 inhibitors.
Roles of Nitric Oxide and Superoxide in Cystitis (R01 DK071085)
7) Investigate the role of urothelial TRPA1 and TRPV1 channels in the initiation of irradiation-induced cystitis.
8) Determine the therapeutic benefits of the hormone, relaxin, in reversing fibrosis and the decreased bladder wall compliance seen in the chronic phase of radiation cystitis.
9) Determine the mechanism of organ cross sensitization where selective irradiation of the colon induces cystitis in the urinary bladder.

   

Kashlan, Ossama

The epithelial sodium channel (ENaC) plays a crucial role in sodium regulation by facilitating sodium detection on the tongue and sodium > reabsorption in the kidney, lung and colon. My research is focused on  the allosteric regulation of ENaC. One area of interest is how channel activity is up-regulated by proteases. Two of the subunits are cleaved twice, releasing inhibitory tracts and activating the channel. Using  electrophysiology, enzymology and molecular modeling, we are characterizing the sites from which these inhibitory tracts originate and how these tracts influence ENaC behavior. Another area of interest  is how sodium down-regulates the channel, a salient feature of the  channel that enables reduced sodium reabsorption during times of  sodium excess. We are using a modeling and molecular evolution approach to examine where sodium binds and how that translates to channel closure.

   

Kleyman, Thomas

The Kleyman laboratory focuses on studies of Na and K channels that are found in epithelia. How are epithelial Na channels regulated by extracellular factors, including Na, shear stress, and proteases? What are the roles of epithelial Na channels in non-epithelial tissues? What are the roles on WNK kinases in facilitating adaptive changes in K channel expression in response to increased dietary K intake?

   

Kullmann, F. Aura

My research focuses on understanding cellular mechanisms underlying various voiding dysfunctions, finding new targets for treatment of these conditions as well as developing and characterizing animal models for voiding dysfunctions. I utilize a combination of in vivo and in vitro methodologies including cystometry, metabolism cages, electrophysiology, single cell imaging, confocal microscopy and immunohistochemistry, to investigate how different components of the urinary bladder, the urothelium, smooth muscle and neurons are affected by pathology. Recent projects are focused on urothelial hyperplasia and regeneration after spinal cord injury in mice and changes in urothelial cell properties in animal models of interstitial cystitis.

   

Ray, Evan

In the research laboratory, we are examining factors that regulate kidney (or renal) sodium excretion, with special focus on the epithelial sodium channel (ENaC).  Increased ENaC activity reduces the sodium excreted in the urine.  Using a combination of electrophysiology, animal modeling, and human clinical data we are exploring the roles played by ENaC in regulating sodium excretion and blood pressure in healthy and diseased kidneys. We are examining whether genetic polymorphisms in the genes encoding ENaC alter blood pressure.  In experimental systems, ENaC can be activated by extracellular proteases.  We are exploring the importance of proteolytic activation of ENaC in vivo in normal physiology and in diseased kidneys.  For example, in nephrotic syndrome, a disorder in which damaged kidneys leak blood stream proteins into the urine, it is possible that blood stream proteases such as plasmin activate ENaC in the kidney, reducing excretion of sodium. We are exploring these and other mechanisms of regulation of ENaC.  Finally, because ENaC is also expressed in the lung, colon, tongue, blood vessels and brain, we are examining what physiologic roles ENaC plays in sodium transport in these organ systems.

   

Roy, Ankita

The renal thiazide-sensitive NaCl cotransporter (NCC; SLC12A3) is expressed in the distal convoluted tubule (DCT), where it plays a key role in salt reabsorption and blood pressure regulation. Several hormones related to disorders of sodium balance such as angiotensin II, aldosterone, vasopressin and insulin increase NCC activity. However, the precise molecular mechanisms that allow these clinically relevant hormones to stimulate NCC are poorly defined.

My previous efforts were focused on deciphering how aldosterone stimulates NCC by

modulating the WNK-SPAK/OSR1 signaling cascade. Currently, I am very keen in investigating how several natriuretic hormones such as insulin, vasopressin, angiotensinII and aldosterone converge upon the WNK signaling pathway to stimulate NCC.

   

Sheng, Shaohu

Dr. Shaohu Sheng is a Research Associate Professor, Dept. of Medicine, University of Pittsburgh School of Medicine. His main research interests are the structure and function relationship, ion regulation and genetic variants of epithelial sodium channel. He is current studying the mechanisms of sodium self-inhibition and the biological effects of genetic variants of the epithelial sodium channel.

   

Shi, Shujie

Mechanically gated ion channels play essential roles in transforming mechanical forces into cellular signals, a biological process referred to as mechanosensation. The focus of my research is to explore mechanisms by which ion channels of the epithelial sodium channel (ENaC)/degenerin family are regulated by mechanical forces. We use the two well-established expression systems, Xenopus oocytes and C. elegans worms, to perform systematic structure-function studies and then translate our findings into a whole animal setting. We discovered that the C. elegans degenerin channel was activated by shear stress and the two pore-forming subunits, MEC-4 and MEC-10 had distinct roles in this response. We are currently working on identifying key domain or sites within the degenerin channel required for the channel's activation by shear stress. We also study how accessory proteins, such as MEC-6 and its mammalian homology PON-2 regulate the channel activity and gating. 

   

Subramanya, Arohan

The goal of our research is to define and understand new molecular pathways that coordinate sodium, chloride, and potassium transport in the kidney and other organs. Our work has provided insights into the pathogenesis of renal salt wasting nephropathies, and identified novel mechanisms involved in the regulation of cell volume, blood pressure, and potassium balance.

   

Tan, Roderick

I am interested in unraveling the molecular mechanisms underlying the development of chronic kidney disease and fibrosis utilizing both in vivo and in vitro approaches. In particular we are assessing novel ways in which the glomerular and tubular compartment cross-talk in disease, and how the Nrf2/Keap1 pathway can be leveraged to prevent CKD. We also study how the Wnt/beta-catenin pathway and matrix metalloproteinases affect renal injury.

   

Truschel, Steven

Age-related changes in cellular function can lead to various human pathologies including cancer, diabetes, and neurodegenerative diseases. A common biomarker of aging cells is a change in the function of lysosomes, which are intracellular organelles responsible for the degradation and recycling of waste material from cellular metabolism and from normal organelle turnover. Impaired lysosomal function can lead to the accumulation of waste products within cells, a progressive loss of lysosomal activity and ultimately cell death. I am interested in understanding how aging affects the lysosomal network within the cells lining the inner surface of the urinary bladder and how these changes affect bladder function.

   

Weisz, Ora

Weisz Lab

We study the regulation of apical membrane traffic in the kidney proximal tubule. Robust apical endocytosis is an essential function of proximal tubule cells and defects in this pathway results in tubular proteinuria that can lead to end stage kidney disease. We are working to identify the compartments and machinery that mediate apical endocytosis in these highly specialized cells, to understand how this pathway is regulated by physiologic stimuli, and to determine the mechanistic basis of genetic disorders and other diseases that result in tubular proteinuria.

   

Zabbarova, Irina

I have over 10 years of experience in studying urinary bladder dysfunction, with a specific interest in mechanisms for the development of bladder dysfunction, especially the one caused by spinal cord injury (SCI) and pelvic organ irradiation (radiation cystitis). Overactive bladder is a common syndrome affecting 16.5% of population in the United States. It has a significant impact on quality of life and is associated with increased health risks and enormous healthcare costs. One of the focuses of our research is the study of the mechanisms that drive lower urinary tract dysfunction following SCI and examination of potential therapeutic options. Radiation cystitis has been also of a particular interest to our lab for a number of years. We have developed a radiation cystitis mouse model which exhibits neurogenic bladder overactivity. With this model, the bladder is briefly withdrawn through a small abdominal incision and irradiated so that other organs are not exposed to ionizing irradiation. Using this model, we have elucidated the mechanisms of radiation-induced damage and demonstrated the therapeutic effect of a number of drugs: existing and developed in collaboration with our colleagues. We have also shown that pelvic irradiation causes organ cross-sensitization, involved in development of pelvic pain/interstitial cystitis, and developed methods for studying its mechanisms.