Yu Research Lab

The Yu laboratory seeks 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 junctions, which consist of large complexes of multiple different proteins. The claudins are a novel family of tight junction membrane proteins that are postulated to form paracellular ion channels. Thus, claudins are likely to be structurally and biophysically different from any known ion channels. There are 27 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 diseases such as acute kidney injury, salt-sensitive hypertension and polycystic kidney disease.

We currently have 4 major projects in the lab:

1. Elucidation of claudin protein structure by X-ray crystallography 

We are a Partner Center of the NIH/NIGMS Protein Structure Initiative: Biology. We collaborate on the expression and crystallography of claudin proteins. Concurrently, we study structure-function relationships using site-directed mutagenesis and functionally characterize wild-type and mutant claudin proteins by electrophysiology and cell biology techniques.

2. Functional role of claudins in the kidney proximal tubule

We are testing the hypotheses that proximal tubule claudins are needed for maximal renal reabsorption of NaCl and other electrolytes, and water and for optimal transport efficiency, using mouse knockout models.

3. Hormonal regulation of renal tubule paracellular permeability

While much is known about the mechanisms by which hormones regulate renal tubule transcellular salt transport, the possibility that these hormones might act via the paracellular route is only just beginning to be recognized and is an understudied area. We use cell culture and animal models to examine the effects of vasopressin, aldosterone and ATP on claudin expression and function.

4. Claudins and cyst growth in polycystic kidney disease

Autosomal dominant polycystic kidney disease is the most common life-threatening genetic disease and is characterized by inexorable growth of kidney cysts due to secretion of chloride and water. We are identifying claudins that uniquely facilitate cyst fluid secretion and could be potential therapeutic targets.

Recent publications:

• 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.
• Engelund MB*, Yu ASL, Li J, Madsen SS, Færgeman NJ, Tipsmark CK. Functional characterization and localization of a gill specific claudin isoform in Atlantic salmon. Am J Physiol Regul Integr Comp Physiol, 302:R300-11, 2012.
• Hou J, Rajagopal M^†, Yu ASL. Claudins and the kidney. Annu Rev Physiol, 2012 Nov 5. [Epub ahead of print]
• Günzel D, Yu ASL. Claudins and the modulation of tight junction permeability. Physiol Rev, in press.

*Graduate student. ^†Postdoctoral fellow.