Paracellular epithelial sodium transport maximizes energy efficiency in the kidney

Abstract

Efficient oxygen utilization in the kidney may be supported by paracellular epithelial transport, a form of passive diffusion that is driven by preexisting transepithelial electrochemical gradients. Claudins are tight-junction transmembrane proteins that act as paracellular ion channels in epithelial cells. In the proximal tubule (PT) of the kidney, claudin-2 mediates paracellular sodium reabsorption. Here, we used murine models to investigate the role of claudin-2 in maintaining energy efficiency in the kidney. We found that claudin-2-null mice conserve sodium to the same extent as WT mice, even during profound dietary sodium depletion, as a result of the upregulation of transcellular Na-K-2Cl transport activity in the thick ascending limb of Henle. We hypothesized that shifting sodium transport to transcellular pathways would lead to increased whole-kidney oxygen consumption. Indeed, compared with control animals, oxygen consumption in the kidneys of claudin-2-null mice was markedly increased, resulting in medullary hypoxia. Furthermore, tubular injury in kidneys subjected to bilateral renal ischemia-reperfusion injury was more severe in the absence of claudin-2. Our results indicate that paracellular transport in the PT is required for efficient utilization of oxygen in the service of sodium transport. We speculate that paracellular permeability may have evolved as a general strategy in epithelial tissues to maximize energy efficiency.

Cell Biology of Tight Junction Barrier Regulation and Mucosal Disease

“…Organ-specific features of tight junction-dependent barrier function have been studied in the lungs (Schlingmann et al 2016), kidneys (Pei et al 2016), and gastrointestinal tract (Wada et al 2013), but have been analyzed in greatest detail in the context of gastrointestinal disease (Clayburgh et al 2005; Heller et al 2005; Weber et al 2008, 2010; Su et al 2009; Marchiando et al 2010a). In vitro, reductionist models of barrier loss in inflammatory bowel disease (IBD) include epithelial responses to exogenous tumor necrosis factor-α (TNF) and interleukin-13 (IL-13), which have each been implicated in Crohn’s disease and ulcerative colitis, the two forms of IBD.…”

Molecular anatomy and functions of the choroidal blood-cerebrospinal fluid barrier in health and disease

“…The paracellular movement of water through the channel forming claudin-2 in choroidal cells may also explain, at least partially, why knocking out aquaporin-1 in mouse decreased CSF secretion only by 35% [103]. The basis for having both a transcellular water pathway through aquaporin and a paracellular water pathway through claudin-2 could be to provide an energy saving mechanism, as shown in the renal proximal tubule [106].…”

Paracellular transport as a strategy for energy conservation by multicellular organisms?

“…6 We found that claudin-2 null mice have similar rates of renal tubule Na C reabsorption (T Na ) to wild-type mice, but that the rate of renal oxygen consumption (QO 2 ) is substantially higher (Fig. 2).…”

“…In our studies we found that this was because the defect in proximal paracellular Na C reabsorption is fully compensated by increased Na C reabsorption further downstream in a tubule segment called the thick ascending limb of Henle's loop. 6 This raised the question of what is the true role of paracellular transport in the proximal tubule. We propose that paracellular transport exists in the proximal tubule because it allows transepithelial transport to be accomplished in a more energy-efficient manner.…”