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-1α (IRE1α), a UPR transducer, regulates proteostasis in GECs. Mice with podocyte-specific deletion of IRE1α (IRE1α KO) were produced and nephrosis was induced with adriamycin. Compared with control, IRE1α KO mice had greater albuminuria. Adriamycin increased glomerular ER chaperones in control mice, but this upregulation was impaired in IRE1α KO mice. Likewise, autophagy was blunted in adriamycin-treated IRE1α KO animals, evidenced by reduced LC3-II and increased p62. Mitochondrial ultrastructure was markedly disrupted in podocytes of adriamycin-treated IRE1α KO mice. To pursue mechanistic studies, GECs were cultured from glomeruli of IRE1α flox/flox mice and IRE1α was deleted by Cre–lox recombination. In GECs incubated with tunicamycin, deletion of IRE1α attenuated upregulation of ER chaperones, LC3 lipidation, and LC3 transcription, compared with control GECs. Deletion of IRE1α 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 IRE1α. The IRE1α pathway is cytoprotective in glomerular disease associated with podocyte injury and ER stress.

肾小球疾病中的肾小球上皮细胞（GEC）/足细胞蛋白稳定失调。展开的蛋白质反应（UPR）是内质网（ER）中的一种适应性途径，可上调蛋白稳态资源。这项研究的特点是机制，UPR换能器需要1α酶（IRE1α）的肌醇调节GEC中的蛋白稳态。产生具有IRE1α（IRE1αKO）足细胞特异性缺失的小鼠，并用阿霉素诱导肾病。与对照组相比，IRE1αKO小鼠具有更高的蛋白尿。阿霉素增加了对照小鼠的肾小球ER伴侣，但这种上调在IRE1αKO小鼠中被削弱。同样，阿霉素治疗的IRE1αKO动物的自噬能力减弱，这可由LC3-II降低和p62升高证明。线粒体超微结构在​​阿霉素治疗的IRE1αKO小鼠的足细胞中显着破坏。为了进行机理研究，从IRE1αflx / flox小鼠的肾小球培养GEC，并通过Cre-lox重组删除IRE1α。与对照GEC相比，在与衣霉素一起孵育的GEC中，IRE1α的缺失减弱了ER伴侣的上调，LC3脂质化和LC3转录。IRE1α的删除减少了最大和ATP链接的耗氧量，以及线粒体膜电位。总之，IRE1α的缺失会损害应激诱导的伴侣产生，自噬和线粒体健康。IRE1α途径在与足细胞损伤和内质网应激相关的肾小球疾病中具有细胞保护作用。从IRE1αflox / flox小鼠的肾小球培养GEC，并通过Cre-lox重组删除IRE1α。与对照GEC相比，在与衣霉素一起孵育的GEC中，IRE1α的缺失减弱了ER伴侣的上调，LC3脂质化和LC3转录。IRE1α的删除减少了最大和ATP链接的耗氧量，以及线粒体膜电位。总之，IRE1α的缺失会损害应激诱导的伴侣产生，自噬和线粒体健康。IRE1α途径在与足细胞损伤和内质网应激相关的肾小球疾病中具有细胞保护作用。从IRE1αflox / flox小鼠的肾小球培养GEC，并通过Cre-lox重组删除IRE1α。与对照GEC相比，在与衣霉素一起孵育的GEC中，IRE1α的缺失减弱了ER伴侣的上调，LC3脂质化和LC3转录。IRE1α的删除减少了最大和ATP链接的耗氧量，以及线粒体膜电位。总之，IRE1α的缺失会损害应激诱导的伴侣产生，自噬和线粒体健康。IRE1α途径在与足细胞损伤和内质网应激相关的肾小球疾病中具有细胞保护作用。IRE1α的删除减少了最大和ATP链接的耗氧量，以及线粒体膜电位。总之，IRE1α的缺失会损害应激诱导的伴侣产生，自噬和线粒体健康。IRE1α途径在与足细胞损伤和内质网应激相关的肾小球疾病中具有细胞保护作用。IRE1α的删除减少了最大和ATP链接的耗氧量，以及线粒体膜电位。总之，IRE1α的缺失会损害应激诱导的伴侣产生，自噬和线粒体健康。IRE1α途径在与足细胞损伤和内质网应激相关的肾小球疾病中具有细胞保护作用。