Endogenous peroxidase was blocked in 35% H2O2 in methanol. StatementThe authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the paper and its Supporting Information files. Abstract Prolonged elevations of plasma aldosterone levels are associated with renal pathogenesis. We hypothesized that renal distress Briciclib could be imposed by an augmented aldosterone-induced protein turnover challenging cellular protein degradation systems of the renal tubular cells. Cellular accumulation of specific protein aggregates in rat kidneys was assessed after 7 days of aldosterone administration. Aldosterone induced intracellular accumulation of 60 s ribosomal protein L22 in protein aggregates, specifically in the distal convoluted tubules. The mineralocorticoid Briciclib receptor inhibitor spironolactone abolished aldosterone-induced accumulation of these aggregates. The aldosterone-induced protein aggregates also contained proteasome 20 s subunits. The partial de-ubiquitinase ataxin-3 was not localized to the distal renal tubule protein aggregates, and the aggregates only modestly colocalized with Briciclib aggresome transfer proteins dynactin p62 and histone deacetylase 6. Intracellular protein aggregation in distal renal tubules did not lead to development of classical juxta-nuclear aggresomes or to autophagosome formation. Finally, aldosterone treatment induced foci in renal cortex of epithelial vimentin expression and a loss of E-cadherin expression, as signs of cellular stress. The cellular changes occurred within high, but physiological aldosterone concentrations. We conclude that aldosterone induces protein accumulation in distal renal tubules; these aggregates are not cleared by autophagy that may lead to early renal tubular damage. Introduction Aldosterone, a steroid hormone with pronounced mineralocorticoid action, is expressed specifically in terrestrial mammals to conserve Na+ and control body fluid volume , . Aldosterone exerts many of its effects via a genomic pathway. Following aldosterone binding to the mineralocorticoid receptor (MR) in the cytoplasm, the aldosterone-receptor complex translocates to the nucleus and induces target gene transcription . The kidney is a major site for regulating Na+ excretion where the hormone regulated fine tuning of the excretion occurs in the distal tubules and collecting ducts. Distal tubules are sub-divided into thick ascending limbs (TAL) and distal convoluted tubules (DCT), which empty into the collecting ducts (CD) through the connecting tubules (CNT). The epithelial cells displays aldosterone sensitivity in the late part of DCT Briciclib (DCT2), the CNT, and the CD . Apart from increasing abundance SIRT3 and/or activity of plasma membrane cation transporters such as the epithelial Na+ channel (ENaC), aldosterone increases the metabolic capacity of its target cells to meet the increased demand of the augmented ion transport rate , . In general, sustained induction of gene transcription and subsequent translation also increases the demand for efficient cellular protein breakdown . Both cytosolic proteins and misfolded or unprocessed Briciclib membrane proteins are degraded in cytosolic proteasomes after polyubiquitination. The misfolded or unprocessed membrane proteins escape the endoplasmatic reticulum (ER) by ER associated degredation (ERAD), which eventually leads to proteasomal degredation of the protein. In order to secure cell survival, the capacity for such degradation can be increased in the unfolded protein response (UPR). However, if this mechanism is saturated, the UPR initiates apoptosis . In cases where the capacity of proteosomal degradation is exceeded, proteins destined for breakdown accumulate in aggregates that, after partial de-ubiquitination by ataxin-3 , are transported to protein structures near the microtubule-organizing center called aggresomes . The proteins accumulated in aggresomes are cleared by autophagosomes and broken down by lysosomes . The accumulation of protein aggregates is a central event in the pathogenesis of several diseases. Some of these conditions.