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Therapeutically enabled mammalian kidney repair and regeneration

ABSTRACT: The kidney has large regenerative capacity that is impeded when injured renal tubular epithelial cells (TECs) undergo SNAI1-driven partial epithelial mesenchymal transition (pEMT). Here we investigate the role of IL11 in TEC pEMT and kidney repair. Wild-type mice with acute kidney injury (AKI) upregulate IL11 in TECs triggering an ERK/P90RSK/GSK3β axis of SNAI1 expression leading to impaired renal function, which is abrogated in Il11 null mice. In mouse models of AKI, a neutralizing IL11 antibody promotes kidney regeneration, while attenuating pEMT, fibrosis and kidney dysfunction. In TECs, TGFβ1 induces autocrine IL11/ERK-dependent pEMT leading to paracrine, IL11-mediated fibroblast activation. Mice with TEC-specific deletion of Il11ra1 are protected from pEMT, inflammation, fibrosis and renal failure. In a mouse model of chronic kidney disease, administration of anti-IL11 reverses fibrosis, regenerates kidney parenchyma and restores renal function. Therapeutic inhibition of IL11 signaling appears permissive for promoting kidney regeneration and improving kidney function.

ORGANISM(S): Homo sapiens

PROVIDER: GSE199080 | GEO | 2022/11/17

REPOSITORIES: GEO

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Glutamine attenuates renal ischemia-reperfusion injury and prevents acute kidney damage

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2023-03-11 | PXD029723 | Pride

Integrated target discovery screens identify IL11 as novel therapeutic target for fibrosis [168 human cardiac fibroblasts]

Project description:Cardiac fibrosis is the final common pathology in heart disease. Here we establish an integrated imaging-genomic discovery platform using primary human heart fibroblasts to identify new drug targets for cardiac fibrosis. Genome wide analyses identify IL11, a secreted cytokine amenable to therapeutic inhibition, as the leading pro-fibrotic candidate. We demonstrate an autocrine loop of IL11 activity that is critical for fibrosis and acts as a nexus of signalling convergence for multiple pro-fibrotic stimuli. IL11 signals in cis and trans via the ERK cascade to activate a programme of fibrosis primarily at the level of protein translation. Injection of IL11 to mice causes fibrosis of the heart, kidney, lung, skin and liver whereas genetic ablation of the IL11 receptor prevented fibrosis across tissues. These data define a new non-canonical fibrogenic pathway and prioritise IL11 as a novel therapeutic target for fibrosis of the heart and other organs

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Integrated target discovery screens identify IL11 as novel therapeutic target for fibrosis [mouse]

2017-11-22 | GSE96991 | GEO

Integrated target discovery screens identify IL11 as novel therapeutic target for fibrosis [human]

2017-11-22 | GSE96975 | GEO

Sirtuin 3 regulates mitochondrial protein acetylation and metabolism in tubular epithelial cells during renal fibrosis

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Immunohistochemical Investigation for Renal Tubules in Adaptive and Maladaptive Repair Process after Renal Tubular Injury in the Kidney of Rats

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IL11 is elevated in systemic sclerosis and IL11-dependent ERK signaling is needed for the profibrotic activity of TGFβ in dermal fibroblasts

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2021-02-22 | GSE162966 | GEO

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