Heterogeneity of tight junctions in the thick ascending limb

Abstract

Renal tubular transport mechanisms are optimized to be energy efficient and tailored to local gradients and transport rates. The combined transcellular action of ion channels, transporters, and pumps, together with the paracellular pathway, enables kidney function. Monogenetic diseases and mouse models indicate that both trans- and paracellular proteins can become disease-causing candidates and may be targets for future therapeutic approaches. Recent advances in tight junction research have provided new insights into their structure, function, and regulation. The thick ascending limb (TAL) is a nephron segment with specific requirements for the paracellular pathway. It has to fuel the generation of the corticomedullary concentration gradient, to be watertight, and to provide a highly selective permeability for Na and divalent cations. Tight junction composition and function in the TAL is organized along the corticomedullary axis. Even on the level of a seemingly homogeneous tubular epithelium like the TAL, there is a separation of tight junction protein expression in the strands between the respective tricellular nexus of the junctional network. Here, we highlight some new insights from our recent work and that of others in this context. In addition, we provide some perspectives for the further study of paracellular transport mechanisms.

Axial and cellular heterogeneity in electrolyte transport pathways along the thick ascending limb

“…It is an important characteristic of TAL epithelium of all species that permeability coefficients for Cl − ( P Cl ) are 2‐10 times lower than those for P Na . As recently summarized by Bleich et al, this cation selectivity is highest in the mTAL ISOM and decreases towards the mTAL OSOM and cTAL . Similarly, transepithelial resistances increase slightly towards the cortex, although absolute resistances vary between species …”

“…Transepithelial resistance across the TAL epithelium is relatively low with 4‐34 Ω · cm 2 , similar to that in the leaky proximal tubule and about 10 times lower than in the early distal convolution . Similarly, permeability coefficients for Na + ( P Na ) in rabbit mTAL ISOM are comparable to those in the proximal convoluted tubule.…”

“…Similarly, permeability coefficients for Na + ( P Na ) in rabbit mTAL ISOM are comparable to those in the proximal convoluted tubule. It is an important characteristic of TAL epithelium of all species that permeability coefficients for Cl − ( P Cl ) are 2‐10 times lower than those for P Na . As recently summarized by Bleich et al, this cation selectivity is highest in the mTAL ISOM and decreases towards the mTAL OSOM and cTAL .…”

“…Transport of NaCl across the TAL epithelium generates a lumen‐positive transepithelial potential difference. This potential difference reaches values of +5 to +13 mV across the mTAL ISOM segment, increasing substantially to about +30 mV in the cTAL . A lumen‐positive transepithelial voltage is generated because the diffusion potential across the apical membrane for K + exceeds the Cl − diffusion potential across the basolateral membrane.…”

“…However, NaCl transport in vivo operates at hypertonic concentrations in the mTAL and at hypotonic concentrations in the cTAL. As it is now clear that mTAL segments express an NKCC2 splice variant with relatively low affinity compared to the high affinity variant in cTAL (discussed in detail below), NaCl transport of perfused tubules may have been undersaturated in mTAL and maximally stimulated in cTAL . The variability in tubule perfusion rates may also significantly affect transport rates between the experiments …”