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Protein-Protein Interactions in Nephrotic Syndrome and Cystic Fibrosis

February 14, 2019

Agnieszka Swiatecka-Urban, MD, FASN, is a tenured associate professor of pediatrics in the Division of Pediatric Nephrology with a secondary appointment in the Department of Cell Biology at the University of Pittsburgh. She joined the Department of Pediatrics and UPMC Children’s Hospital of Pittsburgh in 2007. Dr. Swiatecka-Urban remains clinically active in pediatric nephrology while devoting most of her time to the basic science research of her laboratory, where she investigates aspects of nephrotic syndrome, protein-protein interactions, and the regulation of cell surface stability of transmembrane proteins, most notably in the mechanisms and pathways regulating the cystic fibrosis transmembrane conductance regulator (CFTR) and nephrin. 

Dr. Swiatecka-Urban was a driving force in the creation of the Pittsburgh Nephrotic Syndrome Symposium in 2014 and remains one of the course directors for this CME-accredited, NIH-sponsored symposium, designed to tackle the current clinical challenges of nephrotic syndrome and expand the practice of evidence-based management of the condition. Dr. Swiatecka-Urban also leads the Cure Glomerulonephropathy (CureGN) network cohort study at the University of Pittsburgh — a multicenter, prospective cohort observational study for patients with nephrotic syndrome. 

Nephrin, the Slit Diaphragm, and Nephrotic Syndrome

Dr. Swiatecka-Urban’s research related to nephrotic syndrome, a severe form of kidney disease responsible for approximately 20 percent of cases of pediatric kidney failure, has focused on the protein-protein interactions — specifically the protein nephrin — and how the integrity of the slit diaphragm between the kidney cells called podocytes is dynamically regulated by these protein interactions.

The slit diaphragm is an inter-podocyte junction, and the protein nephrin plays a critical role in regulating how the slit diaphragm functions. In nephrotic syndrome, the slit diaphragm is compromised functionally leading to a steady decrease in kidney function over time. The protein nephrin interacts with other proteins in cells of the slit diaphragm and plays a role in aspects of cell signaling.

“My research on nephrotic syndrome has been focused on identifying novel protein-protein interactions between nephrin, which is a protein that, in a manner, functions like a zipper between podocytes of the slit diaphragm. Podocytes have these different projections on them, the final ones which are finger-like in nature. Nephrin forms very tiny bridges between these finger-like projections, effectively sealing the filtration barrier,” says Dr. Swiatecka-Urban. Dr. Swiatecka-Urban’s research has used a knockout zebra fish model to study the importance of nephrin in kidney formation and function, and its dysregulation leading to nephrotic syndrome.

Protein-Protein Interactions: CFTR and TGF-b b Research

Beyond her nephrotic syndrome research but related to her broader interest in the regulation of cell-surface stability and intra- cellular trafficking of membrane proteins in epithelial cells, Dr. Swiatecka-Urban’s studies have been successful in the characterization of the mechanisms and pathways that regulate the cystic fibrosis transmembrane conductance regulator (CFTR) in order to improve treatment strategies for cystic fibrosis.

Broadly speaking, Dr. Swiatecka-Urban has pursued and helped to uncover aspects of endocytic trafficking pathways of CFTR, protein-protein interactions that regulate CFTR cell surface stability, and lately the mechanisms of TGF-b1 as they relate to signaling in airway epithelial cells. She currently has several NIH-funded studies in progress, including an R01 grant studying high throughput screening for Dab2 inhibitors as stabilizers of CFTR.

Patients with cystic fibrosis have mutations in the CFTR gene that prevent the protein from getting into the plasma membrane and functions as a chloride channel, leading to impaired function.
“Many patients with cystic fibrosis have elevated levels of TGF-b1. Novel protein-protein interactions regulating CFTR and novel mechanisms of the cytokine TGF-b1 signaling are our most recent focus on research related to cystic fibrosis. We hypothesize that the elevated TGF-b1 levels are the roadblock for new treatments — recently FDA-approved molecules that are able to bring the mutant CFTR from inside the cell to the cell membrane but with limited efficiency. TGF-b1 seems to inhibit this process, and the goal is to develop some form of compound that will block or limit TGF-b1 effect,” says Dr. Swiatecka-Urban.

References and Further Reading

1 Swiatecka-Urban, A. Endocytic Trafficking at the Mature Podocyte Slit Diaphragm. Front Pediatr. 2017; 5:32. doi: 10.3389/fped.2017.00032.
2 De Santi C, Gadi S, Swiatecka-Urban A, Greene CM. Identification of Novel Functional miR-143-5p Recognition Element in the Cystic Fibrosis Transmembrame Conductance regulator 3’UTR. AIMS Genetics. 2018; 5(1): 53-62. doi:10.3934/genet.2018.1.53.
3 Farinha CM, Swiatecka-Urban A, Brautigan DL, Jordan P. Front Chem. 2016; Jan 20; 4:1. doi: 10.3389/fchem.2016.00001. Regulatory Crosstalk by Protein Kinases on CFTR Trafficking and Activity.
4 Snodgrass SM, Cihil KM, Cornuet PK, Myerburg MM, Swiatecka-Urban A. TGF-b1 Inhibits CFTR Biogenesis and Prevents Functional Rescue of ΔF508-CFTR in Primary Differentiated Human Bronchial Epithelial Cells. PLoS One. 2013 May 9; 8(5): e63167. doi: 10.1371/journal.pone.0063167.