Tight junction biology and kidney dysfunction

Abstract

The epithelial tight junction (TJ) has three major functions. As a "gate," it serves as a regulatory barrier separating and maintaining biological fluid compartments of different composition. As a "fence," it generates and maintains the apicobasal polarity of cells that form the confluent epithelium. Finally, the TJ proteins form a trafficking and signaling platform that regulates cell growth, proliferation, differentiation, and dedifferentiation. Six examples are selected that illustrate the emerging link between TJ dysfunction and kidney disease. First, the glomerular slit diaphragm (GSD) is evolved, in part, from the TJ and, on maturation, exhibits all three functions of the TJ. GSD dysfunction leads to proteinuria and, in some instances, podocyte dedifferentiation and proliferation. Second, accumulating evidence supports epithelial-mesenchymal transformation (EMT) as a major player in renal fibrosis, the final common pathway that leads to end-stage renal failure. EMT is characterized by a loss of cell-cell contact and apicobasal polarity, which are hallmarks of TJ dysfunction. Third, in autosomal dominant polycystic kidney disease, mutations of the polycystins may disrupt their known interactions with the apical junction complex, of which the TJ is a major component. This can lead to disturbances in epithelial polarity regulation with consequent abnormal tubulogenesis and cyst formation. Fourth, evidence for epithelial barrier and polarity dysregulation in the pathogenesis of ischemic acute renal failure will be summarized. Fifth, the association between mutations of paracellin-1, the first TJ channel identified, and clinical disorders of magnesium and calcium wasting and bovine renal fibrosis will be used to highlight an integral TJ protein that can serve multiple TJ functions. Finally, the role of WNK4 protein kinase in shunting chloride across the TJ of the distal nephron will be addressed.

Effects of calcium oxalate monohydrate crystals on expression and function of tight junction of renal tubular epithelial cells

“…The disruption of tight junction is involved in several diseases, including gastrointestinal, lung and kidney diseases. 22,23 However, to the best of our knowledge, its association with kidney stone disease remains unknown.…”

CLDN16 Genotype Predicts Renal Decline in Familial Hypomagnesemia with Hypercalciuria and Nephrocalcinosis

“…9,19 Following the observation that a naturally occurring knockout model in Japanese black cattle shows early-onset renal failure with diffuse interstitial nephritis, 20 it was recently speculated that claudin-16, like other claudins, may also be involved in the regulation of cell growth, proliferation, differentiation, and dedifferentiation. 21 Hou et al 22 described the functional analysis of claudin-16 in polarized cell lines. They demonstrated that in LLC-PK1 cells, claudin-16 modulated the ion selectivity of the TJ by selectively increasing the permeability of Na ϩ with no effects on Cl Ϫ , resulting in a high permeability ratio of Na ϩ to Cl Ϫ .…”

An SGK1 site in WNK4 regulates Na + channel and K + channel activity and has implications for aldosterone signaling and K + homeostasis

“…Sodium and chloride are reabsorbed by either of two mechanisms: Electroneutral Na-Cl cotransport occurs via the thiazide-sensitive Na-Cl cotransporter (NCC) in the distal convoluted tubule and connecting tubule, and electrogenic Na ϩ reabsorption occurs via the epithelial Na ϩ channel ENaC in the connecting tubule and collecting duct (1). Electrogenic Na ϩ reabsorption provides the electrical driving force for either Cl Ϫ reabsorption via paracellular flux or, alternatively, for K ϩ secretion, which, under normal circumstances, occurs via the renal outer medullary K ϩ channel (ROMK) (2). The key roles of each of these mediators in normal volume, blood pressure, and electrolyte homeostasis is demonstrated by the consequences of mutations that result in increased or diminished activities of these gene products (3).…”