The Yu laboratory seeks to understand the mechanisms of paracellular epithelial transport, its regulation, and its role in the pathogenesis of kidney diseases. Paracellular transport refers to transport in between cells, passing through the tight junctions. It is now well-recognized that paracellular transport is a major route for solutes and water. The claudins are a family of 27 tight junction membrane proteins that form paracellular ion channels. Our investigations of claudin physiology have revealed novel insights into the pathogenesis of acute kidney injury and kidney stone disease.
Role of claudin-2 in kidney stone disease
We recently found a key role for claudin-2 in renal tubule calcium reabsorption. In our studies, claudin-2 global knockout mice have renal calcium wasting, intestinal calcium overabsorption and nephrocalcinosis. Common variants in the human claudin-2 gene increase the risk of kidney stones in the general population. We have also discovered a rare missense mutation in the 2nd extracellular domain in patients that causes hypercalciuria and kidney stone disease in association with obstructive azoospermia and male infertility (manuscript in press in JCI).
Potential lab projects:
- Claudin-2 and epithelial calcium transport
We have made novel gene-targeted mice with a floxed claudin-2 gene that will be used to generate kidney and intestine tissue-specific knockout mice. These will be used to test the role and mechanism of claudin-2 in renal tubule and intestinal calcium transport.
- Claudin-2 and human kidney disease
We are testing the role of claudin-2 expression and gene variants in kidney stone disease using collaborations to obtain human biospecimens from stone patients, and GWAS data from large populations.
- Claudin-5 and glomerular podocyte function
We have made novel mice with a floxed claudin-5 gene by CRISPR-assisted gene targeting. These will be used to generate podocyte-specific claudin-5 knockout mice and test their role in podocyte function, and defense against proteinuric diseases.
- NIH R01 DK115727: Role of claudin-2 in calcium homeostasis and kidney stone disease, PI: Yu (2019-2024)
- NIH R01 DK113111: Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease IV: Prognosis for End-Stage Renal Disease and Biomarker Validation, PI: Yu (2017-2021)
- NIH P20 GM130423: The Kansas Institute for Precision Medicine, MPI: Godwin, Soper, Yu (2018-2023)
Selected Recent Publications:
Curry JN*, Saurette M, Askari M, Pei L*, Filla MB, Beggs MR, Rowe PSN, Fields T, Sommer AJ, Tanikawa C, Kamatani Y, Evan AP, Totonchi M, Alexander RT, Matsuda K, Yu ASL. Claudin-2 deficiency associates with hypercalciuria in mice and human kidney stone disease. J Clin Invest in press
Pei L*, Solis G, Nguyen MT, Kamat N, Magenheimer L, Zhuo M, Li J, Curry J, McDonough AA, Fields TA, Welch WJ, Yu ASL. Paracellular epithelial sodium transport maximizes energy efficiency in the kidney. J Clin Invest, 2016;126: 2509-18.
Weber C, Liang GH, Wang Y, Das S, Lingaraju A, Shen L, Yu ASL, Nelson D, Turner J. Claudin-2 dependent paracellular pores are dynamically gated. eLife 2015;10.7554/e9906
Li J*, Zhuo M, Pei L*, Rajagopal M✝, Yu ASL. Comprehensive cysteine-scanning mutagenesis reveals claudin-2 pore-lining residues with different intrapore locations. J Biol Chem, 289: 6475-84, 2014.
Li J*, Angelow S✝, Linge A, Zhuo M, Yu ASL. Claudin-2 pore function requires an intramolecular disulfide bond between two conserved extracellular cysteines. Am J Physiol Cell Physiol, 2013;305(2):C190-6.
Li J*, Zhuo M, Pei L*, Yu ASL. Conserved aromatic residue confers cation selectivity in claudin-2 and claudin-10b. J Biol Chem, 2013;288(31):22790-7.
*Graduate student. ✝Postdoctoral fellow.
Current Lab Members
Shinsaku Tokuda, MD, Postdoctoral Visiting Scientist
Dr. Tokuda graduated from Kyoto University and did his postdoctoral training in cell biology in the laboratory of Mikio Furuse at Kobe University. He is studying the role of claudins in MDCK cells by developing novel strategies for multi-isoform TALEN-mediated gene targeting. Dr. Tokuda is funded by a Japan Society for the Promotion of Science Overseas Research Fellowship.
Christine Tixier, MS, Research Associate
Christine obtained her Masters degree in Physiology at the University of Arizona, Tucson, and joined KUMC in 2019. As the lab manager for the Yu lab, she manages the mouse colony including breeding, characterization, and in vitro and in vivo studies. She also serves as equipment manager for the Kidney Institute.
Joshua Curry, MD/PhD student, KUMC
Lei Pei, MD, PhD, Clinical Assistant Professor of Medicine, KUMC
Jiahua Li, MD, PhD, Nephrology Fellow, Brigham & Women's Hospital/Harvard Medical School
Robert Ahlstrom, PhD, Medical Science Liaison, Sobi Biopharmaceuticals
Shawn Chi, MS, JD, Associate in Patent Litigation, Weil, Gotshal & Manges LLP
Morten Engelund, PhD, Molecular Biologist, Department of Clinical Genetics, Odense University Hospital, Denmark
Madhumitha Rajagopal, PhD, Medical Student, Albert Einstein College of Medicine
Susanne Angelow, PhD, Senior Manager, Illumina
Shao-Bin Duan, MD, PhD, Professor, Department of Nephrology, Second Xiangya Hospital of Central South University, Changsha, China
Shinichiro Kato, MD, President and CSO, Kirin Pharma USA
Baudouin Leclercq, MD, Nephrologist, Tampa FL
Lara Dowland, PhD, Professor and Chair, Biotechnology/Biomanufacturing Program, Mount Wachusett Community College
Valerie Luyckx, MBBCh, MSc, Affiliate Lecturer, Brigham and Women's Hospital