Inhibition of Cadherin-11 in Chronic Kidney Disease

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PROJECT SUMMARY Chronic kidney disease (CKD) is increasing in prevalence, currently affecting 15% of adults in the United States, and treatment options are extremely limited. CKD arises after an injury to the kidney, which sets off several cellular and molecular events that eventually result in tubulointerstitial fibrosis, the hallmark of CKD. Although many cell types are involved in the development of fibrosis, proximal tubule epithelial cells are integral to the progression of CKD because their high metabolic activity makes them particularly susceptible to injury. Injured epithelial cells secrete pro-fibrotic and -inflammatory cytokines that mediate the recruitment of immune cells and activation of fibroblasts. Therefore, proximal tubule epithelial cells play a significant role in CKD, as they are both a target and mediator of chronic injury. A recent study has shown increased cadherin-11 (CDH11) expression in mouse models of kidney fibrosis as well as in biopsies and urine samples of humans with CKD. Inhibition of CDH11 has proven an effective strategy in several fibrotic diseases, which, combined with the biomarker data, prompted our group to investigate CDH11 in kidney disease. Our preliminary data shows that CDH11 inhibition improves renal function, tubular survival, and kidney morphology in multiple murine models of CKD. In each model, we found disease mitigation when CDH11 was inhibited via both genetic knockout mice and prophylactic administration of a functional blocking antibody. We also found that CDH11 expression was exclusive to injured proximal tubule epithelia in both mice and humans. The mechanism by which CDH11 inhibition protects proximal tubule epithelia is unknown, but CDH11 has been shown to interact with many signaling pathways, including the Wnt/β-catenin pathway. Loss of CDH11 increases canonical Wnt/β-catenin signaling, and our preliminary data suggests such an increase when CDH11 is inhibited in the injured kidney. Wnt/β-catenin signaling in tubular epithelial cells has been linked to reduced tubular injury in CKD models, although the exact role in chronic injury is not well understood. We hypothesize that inhibition of CDH11 will preserve renal function and reduce tubulointerstitial fibrosis in models of CKD in mice through protective effects on the proximal tubule epithelium. Using mouse models of CKD, we will evaluate the effects of CDH11 by analyzing differences between wild type and genetic knockout mice. We will also use isolated proximal tubule cells from wild type and genetic knockout mice to determine the mechanisms by which CDH11 inhibition mitigates renal injury. Finally, we will administer a functional blocking antibody following establishment of injury to evaluate whether CDH11 inhibition could be used as a treatment strategy for CKD. The proposed research will be the first to determine the role of CDH11 in CKD and determine whether CDH11 inhibition could be used as a treatment strategy for CKD.