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Research Article Open Access
Endoplasmic reticulum (ER) stress results from the accumulation of misfolded proteins in the ER. ER stress is associated with acute kidney injury (AKI) of various causes, including two of the major causes of AKI, nephrotoxic drugs and renal ischemia. AKI is a pathology affecting approximately 15% of all hospital stays. When AKI occurs, it results in both significantly increased mortality and increased length of hospital stay. If the patient survives to leave the hospital, it increases the likelihood of developing chronic kidney disease 10-fold, end stage kidney disease 3-fold, and the incidence of premature death 2-fold. An important pathological feature of AKI is the disruption of epithelial cell junctions in the proximal tubule. This loss of epithelial cell junctions disrupts cell polarity preventing the reabsorption of ultrafiltrate components, including sodium, back into the circulation. We hypothesized that ER stress causes epithelial cell disjunction in human proximal tubular cells by trapping the junctional components in the ER and preventing them from reaching the cell surface. ER stress was induced by a variety of stressors including tunicamycin, thapsigargin, and A23187, all of which differ in their mechanism of action. We found that induction of ER stress, by any means, caused epithelial cell disjunction in the renal tubular epithelium. Disjunction was determined by the translocation of β-catenin, which is both a structural component of epithelial cell adherens junctions and a molecular chaperone, from the cell periphery to the perinuclear region. Co-localization experiments found β-catenin to be trapped within the ER.