Claudins and the kidney

Abstract

Claudins are tight-junction membrane proteins that function as both pores and barriers in the paracellular pathway in epithelial cells. In the kidney, claudins determine the permeability and selectivity of different nephron segments along the renal tubule. In the proximal tubule, claudins have a role in the bulk reabsorption of salt and water. In the thick ascending limb, claudins are important for the reabsorption of calcium and magnesium and are tightly regulated by the calcium-sensing receptor. In the distal nephron, claudins need to form cation barriers and chloride pores to facilitate electrogenic sodium reabsorption and potassium and acid secretion. Aldosterone and the with-no-lysine (WNK) proteins likely regulate claudins to fine-tune distal nephron salt transport. Genetic mutations in claudin-16 and -19 cause familial hypomagnesemic hypercalciuria with nephrocalcinosis, whereas polymorphisms in claudin-14 are associated with kidney stone risk. It is likely that additional roles for claudins in the pathogenesis of other types of kidney diseases have yet to be uncovered.

Keywords: calcium; calcium-sensing receptor; cell and transport physiology; epithelial; renal proximal tubule cell; renal tubular epithelial cells; sodium transport.

Figure 1.

Structure of a claudin-15 monomer, viewed from just above the plane of the membrane. Four transmembrane αhelices (blue) traverse the lipid bilayer. The first extracellular domain contributes four β strands (yellow) to the β-sheet structure and a short extracellular helix (red), while the second extracellular domain contributes the fifth β strand (green). The β sheet forms an inward-facing palm that likely lines the pore pathway. Image of protein databank ID: 4P79 (ref. 17) created with visual molecular dynamics 1.9.1 (ref. 115).

Figure 2.

Localization of claudins along the adult mammalian renal tubule. Captions shaded in gray summarize some of the key physiologic functions of each nephron segment. AVP, arginine vasopressin; TGF, tubuloglomerular feedback. Refer to Table 1 for references.

Figure 3.

Physiologic roles of claudins in renal tubule epithelia. (A) Proximal tubule. Na⁺ reabsorption by Na⁺-H⁺ exchange or coupled to organic solutes, such as glucose, generates a high luminal Cl⁻ concentration and negative transepithelial voltage that drives paracellular Cl⁻ reabsorption. The subsequent lumen-positive voltage drives Na⁺ reabsorption through claudin-2. (B) Thick ascending limb. Transcellular Na reabsorption via the Na-K-2Cl cotransporter with K⁺ recycling via an apical K⁺ channel generates a lumen-positive voltage. This is further augmented by the tendency of reabsorbed Na⁺ to backflux through Na⁺-selective paracellular pores, postulated to be formed by claudin-16 and -19. This voltage drives Ca²⁺ and Mg²⁺ reabsorption paracellularly. The CaSR regulates paracellular transport by a cascade involving calcineurin, micro-RNAs, and claudin-14. (C) Collecting duct. Na⁺ is reabsorbed electrogenically via an apical epithelial Na⁺ channel in principal cells. The paracellular pathway, proposed to be constituted by claudin-4, -7, and/or -8, acts as a barrier to prevent backflux of reabsorbed Na⁺ (as well as secreted K⁺ and H⁺) while allowing Cl⁻ to diffuse down its electrical gradient. In each panel, the lumen is on the left and peritubular space on the right.