Biology of claudins

Abstract

Claudins are a family of tight junction membrane proteins that regulate paracellular permeability of epithelia, likely by forming the lining of the paracellular pore. Claudins are expressed throughout the renal tubule, and mutations in two claudin genes are now known to cause familial hypercalciuric hypomagnesemia with nephrocalcinosis. In this review, we discuss recent advances in our understanding of the physiological role of various claudins in normal kidney function, and in understanding the fundamental biology of claudins, including the molecular basis for selectivity of permeation, claudin interactions in tight junction formation, and regulation of claudins by protein kinases and other intracellular signals.

Fig. 1.

Alignment of the 1st extracellular domains of claudins. Acidic residues are highlighted in red, basic residues in blue. Claudins that have been shown to act as cation-selective pores are marked with yellow. Arrows indicate conserved regions that contain only positively charged residues (blue arrows) or both positively and negatively charged residues (striped arrows). Boxes indicate positions at which mutations have been shown to decrease or abolish claudin function; residues that have been mutated without loss of function are underlined. Data are from Refs. , , , and except for claudin-2 (our unpublished observations).

Fig. 2.

Localization and putative function of claudin proteins in mammalian kidney. Localization data were summarized from the following studies: claudins-1, -3,- 4, and -11 (59), claudin-2 (28), claudin-6 (1, 6, 118), claudins-7 and -8 (68), claudin-9 (1), claudin-10 (108), claudin-14 (12), claudin-16 (61, 91), and claudin-19 (6, 61). Tubule expression of claudins-6 and -9 are only found in neonatal kidney (1). Many of these claudins have not been rigorously examined in all nephron segments, so the data shown are not comprehensive. Macula densa claudin expression is from our own unpublished results. Claudins-5 and -15 are confined to endothelial cells of the vasculature and glomeruli (59) and so are not shown. Claudins-12, -18, and -20 to -24 have not yet been examined. Claudins are color coded according to their putative charge selectivity and permeability. Figure modified from Angelow S, Yu AS. Curr Opin Nephrol Hypertens 16: 459–464, 2007 (copyright Lippincott, Williams & Wilkins, 2007).