Harry Statland and Solon Summerfield Professor of Medicine
Director, Kidney Institute
Department of Internal Medicine, Nephrology Division
M.B., B.Chir., University of Cambridge, United Kingdom
Fellowship, Brigham and Women’s Hospital, 1990-1994
Publications: Click here
Renal tubule transport of salts, minerals and water Paracellular transport, and the role of tight junction proteins Disorders of mineral metabolism (calcium and magnesium)
1. Claudins and paracellular transport
A current focus of the laboratory is to understand the molecular and structural basis of paracellular epithelial transport and its regulation. Paracellular transport refers to transport in between cells. It is now well-recognized that paracellular transport is a major route for vectorial transport of solutes and water. The rate-limiting step in paracellular transport (the paracellular "barrier") is constituted by the tight junction, which is the most apical of the intercellular junctions. Tight junctions consist of large complexes of multiple different proteins. The claudins are a novel family of tight junction proteins that are postulated to form paracellular ion channels. If correct, claudins would likely be structurally and biophysically different from any known ion channels. There are at least 20 different claudin isoforms, raising the exciting possibility that isoform-specific expression may be responsible for the variability in paracellular permeability properties of different epithelial tissues. Investigation of claudin physiology promises to reveal novel insights into the pathogenesis of clinical renal diseases associated with disturbances of the paracellular barrier, such as oliguric acute tubular necrosis, ischemic allograft dysfunction, and certain forms of salt-sensitive hypertension, including pseudohypoaldosteronism, Type II (Gordon's syndrome). We are currently actively investigating the function of these proteins by overexpressing them in cell culture monolayers and performing electrophysiological and tracer flux measurements in Ussing chambers, and by site-directed mutagenesis of key residues in the putative pore-lining region.
2. WNK kinases and renal tubule NaCl reabsorption
WNK1 and WNK4 are serine-threonine kinases that regulate transcellular and possibly paracellular salt transport in the distal renal tubule. Mutations in these kinases cause pseudohypoaldosteronism, Type II (PHAII), which is characterized by salt-sensitive hypertension with hyperkalemia. WNKs seem to have broad regulatory roles in the distal tubule epithelium, but the mechanism underlying the pathogenesis of PHAII is still incompletely understood. We are currently exploring the substrates of WNK4 phosphorylation. In collaboration with Dr. Alicia McDonough in the Department of Cell and Neurobiology, we are investigating the role of angiotensin II and reactive oxygen species in the regulation of a key downstream effector of WNK kinases, the thiazide-sensitive NaCl cotransporter, NCC.
Yu ASL, Kanzawa SA, Usorov A, Lantinga-van Leeuwen IS, Peters DJM. Tight junction composition is altered in the epithelium of polycystic kidneys. J Pathol 216(1):120-128, 2008.
Yu ASL, Cheng, MH, Angelow S, Günzel D, Kanzawa SA, Schneeberger EE, Fromm M, Coalson RD. Molecular basis for cation selectivity in claudin-2-based paracellular pores: Identification of an electrostatic interaction site. J Gen Physiol, 133: 111-127, 2009.
Ahlstrom R, Yu ASL. Characterization of the kinase activity of a WNK4 protein complex. Am J Physiol Renal Physiol, 297(3):F685-92, 2009.
Angelow S, Yu ASL. Structure-function studies of claudin extracellular domains by cysteine-scanning mutagenesis. J Biol Chem, 284(42):29205-17, 2009.
Yu ASL, Cheng MH, Coalson RD. Calcium inhibits paracellular sodium conductance through claudin-2 by competitive binding. J Biol Chem, 285(47):37060-9, 2010.
Fazlollahi F, Angelow S, Yacobi NR, Marchelletta R, Yu AS, Hamm-Alvarez SF, Borok Z, Kim KJ, Crandall ED. Polystyrene nanoparticle trafficking across MDCK-II. Nanomedicine. 2011 Feb 7. [Epub ahead of print]