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TNF-α induces Claudin-1 expression in renal tubules in Alport mice

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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… Click to show full 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.

Keywords: proximal tubules; kidney; proximal tubular; expression; alport mice

Journal Title: PLoS ONE
Year Published: 2022

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