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Autophagy regulated by the HIF/REDD1/mTORC1 signaling is progressively increased during erythroid differentiation under hypoxia

ABSTRACT: For hematopoietic stem and progenitor cells (HSPCs), hypoxia is a specific microenvironment known as the hypoxic niche. The role of hypoxia in maintaining quiescence, self-renewal and proliferation of HSPCs has been more elaborated. What remains unclear is the regulation of hypoxia on HSPC differentiation, especially on the differentiation of HSPCs into erythrocytes. In this study, we show that hypoxia evidently accelerates erythroid differentiation, and in this process effectively enhances autophagy which rapidly supplies cellular components through degradation of organelles or proteins to meet the needs of cell stress or development. In order to ascertain whether autophagy mediates the erythroid differentiation promoted by hypoxia, we analyze the perturbation of erythroid differentiation after pharmacological and genetic interference with autophagy, and address that autophagy is required for hypoxia-accelerated erythroid differentiation. Transcriptomics reveals HIF-1 and mTORC1 pathways may function as the upstream of autophagy to regulate erythroid differentiation under hypoxia. We further determine that mTORC1 signaling is suppressed by hypoxia to relieve its inhibition of autophagy. In addition, we also discover a new regulatory pattern that with the process of erythroid differentiation, mTORC1 activity gradually decreases and autophagy activity increases concomitantly. Moreover, we provide evidence that HIF-1 target gene REDD1, which inhibits mTORC1 activity, is dramatically upregulated under hypoxia. Silencing REDD1 expression activates mTORC1 signaling and impairs the enhanced autophagy and the accelerated erythroid differentiation under hypoxia. Together, our study reveals that hypoxia is conductive to accelerating erythroid differentiation, in which autophagy induced by the HIF-1/REDD1/mTORC1 pathway plays a pivotal role.

ORGANISM(S): Homo sapiens

PROVIDER: GSE199778 | GEO | 2022/04/04

REPOSITORIES: GEO

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Project description:Renal hypoxia is widespread in acute kidney injury (AKI) of various aetiologies. Hypoxia adaptation, conferred through the hypoxia-inducible factor (HIF), appears to be insufficient. Here we show that HIF activation in renal tubules through Pax8-rtTA-based inducible knockout of von Hippel-Lindau protein (VHL-KO) protects from rhabdomyolysis-induced AKI. In this model, histological observations indicate that injury mainly affects proximal convoluted tubules, with 5% necrosis at d1 and 40% necrosis at d2. HIF-1alpha up-regulation in distal tubules reflects renal hypoxia. However, lack of HIF in proximal tubules suggests insufficient adaptation by HIF. AKI in VHL-KO mice leads to prominent HIF activation in all nephron segments, as well as to reduced serum creatinine, serum urea, tubular necrosis, and apoptosis marker caspase-3 protein. At d1 after rhabdomyolysis, when tubular injury is potentially reversible, HIF mediated protection in AKI is associated with activated glycolysis, cellular glucose uptake and utilization, autophagy, vasodilation, and proton removal as demonstrated by qPCR, pathway enrichment analysis and immunohistochemistry. Together, our data provide evidence for a HIF-orchestrated multi-level shift towards glycolysis as a major mechanism for protection against acute tubular injury. All experiments were carried out in transgenic mice in which selective renal tubular VHL knockout (VHL-KO) was inducible by doxycycline (Reference: Mathia S, Paliege A, Koesters R, Peters H, Neumayer HH, Bachmann S, Rosenberger C. Action of hypoxia-inducible factor in liver and kidney from mice with Pax8-rtTA-based deletion of von Hippel-Lindau protein. Acta Physiol (Oxf). 2013; 207(3):565-76.). Four groups of animals were used: 1) controls: untreated mice; 2) VHL-KO: injected with doxycycline (0.1 mg per 10 g body weight SC), 4 days prior to sacrifice; 3) AKI: rhabdomyolysis; 4) VHL-KO/AKI: doxycycline plus rhabdomyolysis. To induce AKI, 50% glycerol (0.05 ml per 10 g body weight) was injected IM into the left hind limb under isoflurane narcosis. Drinking water was withdrawn between 20 h prior and 24 h after glycerol injection.

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Autophagy regulated by the HIF/REDD1/mTORC1 signaling is progressively increased during erythroid differentiation under hypoxia

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