Interleukin-22 in kidney regeneration

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The capacity to regenerate renal tissue determines outcomes of acute kidney injury (AK) and chronic kidney disease (CKD). Recent data document that intrarenal mononuclear phagocytes (diverse dendritic cell and macrophage phenotypes) not only drive kidney injury but also kidney regeneration but the associated pro-regeneratory mediators remain unknown. Using a newly developed screening system we identified the recently discovered interleukin IL-22 as such a potential mediator. Our project-specific preliminary data demonstrate that dying tubular epithelial cells release TLR4 agonistic components that stimulate renal dendritic cells to secrete IL-22. IL-22 accelerates the regeneration of of injured tubular cells via IL-22R-mediated MAPK and Erk signaling. Currently, there are no published data on IL-22 and the kidney. In this project we plan to study this previously unknown mechanism of kidney regeneration. We plan to: 1. Study the expression of IL-22 and IL-22R in the following animal models: post-ischemic AKI followed bei either full recovery (AKI) or by progressive tubular atrophy and fibrosis (CKD), aristolochic acid-induced AKI/CKD, and renal fibrosis upon unilateral ureteral obstruction. 2. To study the regulation of IL-22 induction including the effect of TLR agonists, Ahr agonists, and Notch agonists. 3. Characterizing the IL-22-mediated regeneration of tubular epithelial cells, tubular progenitor cells, renal endothelial cells, and renal fibroblasts in vitro. In addition we will study this aspect in vivo using IL-22-deficient mice, IL-22 neutralizing antibodies, depletion of IL-22-producing immune cell subsets, and reconstitution with recombinant IL-22. 4. Finally, we will evaluate the therapeutic potential of recombinant IL-22 on the aforementioned mouse models of kidney injury. We expect that data from this project will overt a previously unknown mechanism of kidney regeneration. Most importantly, this mechanism holds the potential for therapeutic applications, e.g. to accelerate AKI recovery and to slow down the progression of CKD with recombinant IL-22 or other IL-22R agonists.