Role of IRE1? in podocyte proteostasis and mitochondrial health.

ABSTRACT: Glomerular epithelial cell (GEC)/podocyte proteostasis is dysregulated in glomerular diseases. The unfolded protein response (UPR) is an adaptive pathway in the endoplasmic reticulum (ER) that upregulates proteostasis resources. This study characterizes mechanisms by which inositol requiring enzyme-1? (IRE1?), a UPR transducer, regulates proteostasis in GECs. Mice with podocyte-specific deletion of IRE1? (IRE1? KO) were produced and nephrosis was induced with adriamycin. Compared with control, IRE1? KO mice had greater albuminuria. Adriamycin increased glomerular ER chaperones in control mice, but this upregulation was impaired in IRE1? KO mice. Likewise, autophagy was blunted in adriamycin-treated IRE1? KO animals, evidenced by reduced LC3-II and increased p62. Mitochondrial ultrastructure was markedly disrupted in podocytes of adriamycin-treated IRE1? KO mice. To pursue mechanistic studies, GECs were cultured from glomeruli of IRE1? flox/flox mice and IRE1? was deleted by Cre-lox recombination. In GECs incubated with tunicamycin, deletion of IRE1? attenuated upregulation of ER chaperones, LC3 lipidation, and LC3 transcription, compared with control GECs. Deletion of IRE1? decreased maximal and ATP-linked oxygen consumption, as well as mitochondrial membrane potential. In summary, stress-induced chaperone production, autophagy, and mitochondrial health are compromised by deletion of IRE1?. The IRE1? pathway is cytoprotective in glomerular disease associated with podocyte injury and ER stress.

SUBMITTER: Navarro-Betancourt JR 

PROVIDER: S-EPMC7677398 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature