Under pathological conditions, kidney is subjected to multiple toxic, ischemic and immunological failures that promote the occurrence of chronic kidney disease and the development of acute kidney injury. In response to stress, renal parenchymal cells activate biological adaptive processes permitting the maintenance of cell viability and renal homeostasis. These adaptive responses can also activate innate immunity and induce tissue remodeling (fibrogenesis and angiogenesis). However, accurate mechanisms of this regulation are still unclear. The aim of this work was to characterize regulation mechanisms and micro environmental consequences(inflammation and angiogenesis) of the activation of the UPR (Unfolded Protein Response) and autophagy, in response to ischemic and immunological stress. In a first study, we demonstrated that the UPR is involved in the generation of inflammatory response induces by metabolic stress in tubular renal cells. Metabolic stress, characterized by glucose deprivation, induces an ER stress and activates the UPR. This stress activates NF-.B and promotes the transcription of pro inflammatory cytokines and chemokines. The PERK signaling is not required for the induction of inflammation but amplifies cytokine expression whereas IRE1 is involved in the generation of inflammatory response. Moreover, acute ischemia activates ER stress and inflammation in rat kidneys. Finally, from kidney transplant biopsies performed before implantation, the expression of GRP78, an ER stress marker, and NF-.B p65/RelA in renal tubules is significantly increased in comparison with stable human kidney transplant biopsies. In a second study, we showed that the UPR regulates angiogenesis in tubular renal cells during glucose deprivation. The PERK pathway is a major regulator of angiogenic factors expression (VEGFA, bFGF and angiogenin). Furthermore, angiogenin expression is modulated by PERK and IRE1. pathways. Finally, acute ischemia activates the UPR and, in parallel, increases VEGFA, bFGF and angiogenin expression in rat kidneys. In a third work, we identified a novel mechanism by which IFN. activates autophagy in human kidney epithelial cells. We showed that IFN. promotes tryptophan depletion, activates the eIF2. kinase GCN2, and leads to an increase of the autophagic flux. Moreover, tryptophan supplementation and RNA interference directed against GCN2 inhibit IFN.-induced autophagy. Finally,autophagy regulates the secretion of inflammatory cytokines and growth factors in response to IFN..In conclusion, we characterized in this work original mechanisms that regulate inflammatory and angiogenic responses by the UPR and autophagy in response to ischemic and immunological stress in tubular renal human epithelium.
