Abstract
Claudin-1 (CL-1) is responsible for the paracellular barrier function of glomerular parietal epithelial cells (PEC) in kidneys, but the role of CL-1 in proximal tubules remains to be elucidated. In this study, to evaluate CL-1 as a potential therapeutic drug target for chronic kidney disease, we investigated change of CL-1 expression in the proximal tubules of diseased kidney and elucidated the factors that induced this change. We established Alport mice as a kidney disease model and investigated the expression of CL-1 in diseased kidney using quantitative PCR and immunohistochemistry (IHC). Compared to wild type mice, Alport mice showed significant increases in plasma creatinine, urea nitrogen and urinary albumin excretion. CL-1 mRNA was increased significantly in the kidney cortex and CL-1 was localized on the adjacent cell surfaces of PECs and proximal tubular epithelial cells. The infiltration of inflammatory cells around proximal tubules and a significant increase in TNF-α mRNA were observed in diseased kidneys. To reveal factors that induce CL-1, we analyzed the induction of CL-1 by albumin or tumor necrosis factor (TNF)-α in human proximal tubular cells (RPTEC/TERT1) using quantitative PCR and Western blotting. TNF-α increased CL-1 expression dose-dependently, though albumin did not affect CL-1 expression in RPTEC/TERT1. In addition, both CL-1 and TNF-α expression were significantly increased in UUO mice, which are commonly used as a model of tubulointerstitial inflammation without albuminuria. These results indicate that CL-1 expression is induced by inflammation, not by albuminuria in diseased proximal tubules. Moreover, we examined the localization of CL-1 in the kidney of IgA nephropathy patients by IHC and found CL-1 expression was also elevated in the proximal tubular cells. Taken together, CL-1 expression is increased in the proximal tubular epithelial cells of diseased kidney. Inflammatory cells around the tubular epithelium may produce TNF-α which in turn induces CL-1 expression.
Highlights
Tight junctions (TJ) play an important role in sealing adjacent cells and forming epithelial barriers in various tissues, such as intestine and skin, to limit paracellular permeability
We designed a pair of zinc finger nuclease mRNAs that target the nucleotide sequence in exon 48 of mouse endogenous Col4a3 (Fig 1A)
We investigated the expression of CL-1 in diseased renal tubules using Alport mice as a chronic kidney disease (CKD) model
Summary
Tight junctions (TJ) play an important role in sealing adjacent cells and forming epithelial barriers in various tissues, such as intestine and skin, to limit paracellular permeability. In a study using anti-glomerular basement membrane (GBM) mice, the reduction of CL-1 caused a decline in paracellular permeability in adjacent PECs. The authors suggested that CL-1 seals PECs by forming TJ and works as a second barrier to prevent the leakage of filtrated protein into the extraglomerular space [11]. It has been shown that CL-1 expression is increased in the LPS-induced acute nephritis model [15], and that albuminuria or hypotonic stress decreases CL-1 expression in tubular cells [16, 17]. Based on these contradictory studies, the role of CL-1 in proximal tubules in kidney disease remains controversial. We investigated the change of CL-1 expression in Alport mice and explored the role and inducing factors of CL-1 in proximal tubule
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