Alan Yu, MD

Professor and Director
Kidney Institute Director
School of Medicine, Internal Medicine

University of Cambridge, England, B.A. (Honors, Class I), Medical Sciences
University of Cambridge, England, M.B., B.Chir. (Distinction), Medicine
Research Fellow in Nephrology, Brigham & Women's Hospital and Harvard Medical School
Residency in Internal Medicine, Physician-Scientist Track, Brigham & Women's Hospital
Clinical Fellow in Nephrology, Brigham & Women's Hospital

Publications: Click here

Research Focus

Renal tubule transport of salts, minerals and water Paracellular transport, and the role of tight junction proteins Disorders of mineral metabolism (calcium and magnesium)

Yu Lab web site
Publications

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.