Regulation of colitis associated with acute kidney injury by the Wnt pathway

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Summary: Renal manifestations or urinary complications occur in 4–23% in patients with Crohn’s disease (CD) and ulcerative colitis (UC) (forms of inflammatory bowel disease, IBD), often in those with severe, long- standing disease. Prevention and treatment of IBD and associated acute kidney injury (AKI) are important clinical problems, but molecular targets for therapeutic immune intervention remain elusive. There is critical need for understanding the immunological mechanisms of colitis-mediated AKI that will guide in identifying new targets for the prevention or treatment of IBD and IBD-associated AKI. We have identified a new and previously unsuspected role for the canonical Wnt pathway as a key molecular pathway in regulating cross‐talk between the gut and kidney during disease progression. We show that Wnt ligands that signal through low- density lipoprotein receptor-related protein 5 and 6 (LRP5/6) in renal antigen presenting cells (APCs) is critical for suppressing pathologic inflammatory response in the kidney and colitis-mediated AKI. Ablation of these co- receptors in DCs or MPs in mice causes loss of immune homeostasis and augments colitis-mediated AKI. However, downstream mechanisms by which LRP5/6 acts in renal APCs act to suppress inflammation and AKI are completely unknown. Specific aims in the current proposal are (Aim 1) to understand how the canonical Wnt pathway imparts regulatory phenotype on renal APCs and suppresses colitis-mediated AKI; (Aim2) to understand how IL-10 and retinoic acid produced by renal APCs in response to canonical Wnt signaling suppresses oxidative stress in the kidney and colitis-mediated AKI, and (Aim3) to examine the “proof of concept” that pharmacological activation of the canonical Wnt pathway prevents renal inflammation and colitis- mediated AKI. The successful completion of the proposed studies will significantly enhance our understanding of the mechanisms by which the canonical Wnt control inflammatory responses in the intestine. Importantly, the proposed studies will provide new avenues to enhance anti-inflammatory response of Wnt signaling while suppressing pathologic inflammatory response that may have significant therapeutic impact in treating IBD- associated AKI and other immune mediated-renal diseases.