DS0403 -

Angiogenin, a novel mediator of the Endoplasmic Reticulum stress response in the kidney – TRANSLATE

Submission summary

Chronic kidney disease (CKD) affects millions of persons worldwide and constitutes a major public health problem. Therefore, understanding the molecular basis of CKD is a key challenge for the development of preventive and therapeutic strategies. A major contributor to chronic histological damage associated with CKD is acute kidney injury (AKI), for instance, ischemia-reperfusion (I/R) injury. At the cellular level, AKI is associated with microenvironmental alterations, forcing cells to activate adaptive biological processes that eliminate the stressor and generate alarm signals. These signaling pathways actively participate in tissue remodeling by promoting inflammation and fibrogenesis, ultimately leading to CKD. Many stresses that are encountered upon kidney injury are prone to trigger endoplasmic reticulum (ER) stress. In the kidney, ER stress fosters AKI and participates in chronic histological damage. Angiogenin is a secreted ribonuclease that cleaves transfer RNA to generate fragments called tiRNA, which contribute to stress-induced translational repression. Angiogenin is also secreted in the extracellular medium. Whether angiogenin signaling is integrated in the ER stress response and is involved in chronic histological changes subsequent to AKI is currently unknown.

We have recently provided evidence that angiogenin is a critical regulator of the adaptation to ER stress-induced AKI; that secreted angiogenin behaves like an alarmin and influences macrophages toward a proinflammatory phenotype; and that urinary angiogenin could be a potential marker of kidney injury.

The hypothesis that we are testing is that angiogenin, once secreted by renal epithelial cells upon ER stress associated with AKI, shapes macrophages toward a proinflammatory and fibrotic phenotype, which in turn will foster maladaptive tissue remodeling and chronic histological changes ultimately leading to CKD. The objectives of the present proposal are as follows: (1) to determine the contribution of angiogenin to the chronic histological changes that occur after ER stress-induced AKI, including I/R injury; (2) to determine the mechanisms by which angiogenin activates macrophages and how they impact chronic histological changes following AKI; and (3) to determine the clinical relevance of urinary angiogenin levels in individuals with AKI in predicting subsequent CKD.

We will combine molecular and cellular biology approaches with genetically engineered murine models of AKI in addition to an analysis of human urine from individuals with I/R injury to investigate the molecular basis of angiogenin-mediated contribution to the signaling and biological outcomes of ER stress in the kidney. Models of AKI associated with ER stress will be created using tunicamycin injections and I/R injury. Genetically engineered mice (constitutive knocked-out, and tubule-specific transgenic mouse which cannot secrete angiogenin) will be analyzed to determine how secreted angiogenin influences macrophage phenotypic changes and contributes to CKD following AKI. Human macrophages in culture will be used to provide mechanistic insights into how angiogenin activates macrophages and to determine whether tiRNA is implicated in this process. Finally, we will monitor the concentrations of angiogenin in urine from two large cohorts of individuals with AKI (kidney transplant recipients and cardiac surgery patients) to determine if the urinary concentrations of angiogenin are predictive of subsequent CKD.

We expect to demonstrate that angiogenin is a new mediator of the ER stress response in the kidney that participates in a novel biological stress response implicated in the pathophysiology of AKI and subsequent CKD. This project will result in the development of new monitoring tools and will improve the care of patients with renal disease.

Project coordination

Nicolas Pallet (Université Paris Descartes - Laboratoire Médecine personnalisée, Pharmacogénomique, Optimisation thérapeutique)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.


UPD - UMRS 1147 Université Paris Descartes - Laboratoire Médecine personnalisée, Pharmacogénomique, Optimisation thérapeutique

Help of the ANR 219,744 euros
Beginning and duration of the scientific project: - 36 Months

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