title: Distal renal tubules are deficient in aggresome formation and autophagy upon aldosterone administration.
abstract: Prolonged elevations of plasma aldosterone levels are associated with renal pathogenesis. We hypothesized that renal distress 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 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 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.
authors.affiliation: Department of Biomedicine, Membranes Center & InterPrET Pilot Center, Health, Aarhus University, Aarhus, Denmark.
authors.forename: Muhammad Umar
authors.initials: MU
authors.lastname: Cheema
authors.affiliation: Department of Biomedicine, Membranes Center & InterPrET Pilot Center, Health, Aarhus University, Aarhus, Denmark.
authors.forename: Helle Hasager
authors.initials: HH
authors.lastname: Damkier
authors.affiliation: Department of Biomedicine, Membranes Center & InterPrET Pilot Center, Health, Aarhus University, Aarhus, Denmark.
authors.forename: Jakob
authors.initials: J
authors.lastname: Nielsen
authors.affiliation: Department of Molecular Biology and Genetics, iNano, Science and Technology, Aarhus University, Aarhus, Denmark.
authors.forename: Ebbe Toftgaard
authors.initials: ET
authors.lastname: Poulsen
authors.affiliation: Department of Molecular Biology and Genetics, iNano, Science and Technology, Aarhus University, Aarhus, Denmark.
authors.forename: Jan J
authors.initials: JJ
authors.lastname: Enghild
authors.affiliation: Department of Biomedicine, Membranes Center & InterPrET Pilot Center, Health, Aarhus University, Aarhus, Denmark.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Fenton
authors.affiliation: Department of Biomedicine, Membranes Center & InterPrET Pilot Center, Health, Aarhus University, Aarhus, Denmark.
authors.forename: Jeppe
authors.initials: J
authors.lastname: Praetorius
mesh_terms: D000450:Aldosterone / Q000008:administration & dosage* / Q000494:pharmacology*; D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D015220:Calcium Channels / Q000378:metabolism; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006655:Histone Deacetylases / Q000378:metabolism; D007686:Kidney Tubules, Distal / Q000166:cytology* / Q000187:drug effects / Q000276:immunology*; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology; D008297:Male; D008870:Microtubules / Q000187:drug effects* / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D066329:Protein Aggregates / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D059748:Proteolysis / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D054683:Ribosome Subunits, Large, Eukaryotic / Q000378:metabolism; D014746:Vimentin / Q000378:metabolism
chemical_list: D015220:Calcium Channels; D066329:Protein Aggregates; D014746:Vimentin; D000450:Aldosterone; D046988:Proteasome Endopeptidase Complex; D006655:Histone Deacetylases