Chronic kidney disease (CKD) affects more than 13% of the population, and its prevalence in the United States is increasing. Regardless of the underlying etiology, CKD tends to progress once renal function falls below 50%. Glomerulosclerosis is a hallmark of CKD of all etiologies, suggesting that diverse primary diseases engage common final pathways of disease progression. Unfortunately, there are currently no specific therapies for slowing the progression of CKD and glomerulosclerosis. Interestingly, it has been known for decades that IgM and C3 are deposited in the glomeruli of some patients with CKD, although the significance of these deposits has remained elusive. Recent work has revealed that natural IgM (i.e. IgM that has not undergone somatic mutation) binds to neoepitopes expressed on injured cells. The tissue-bound IgM activates the complement system, contributing to further injury. This discovery prompted us to reexamine the significance of glomerular IgM deposits in patients with CKD. We have found that IgM binds to specific epitopes expressed in the glomeruli of mice after chemical, inflammatory, and ischemic injury. The glomerular IgM triggers complement activation, causing further renal injury. Our preliminary data also demonstrates that complement activation fragments are elevated in the plasma of human patients with CKD. The overall hypothesis of the current proposal is that natural antibody IgM binds to neoepitopes expressed in the glomerulus after a wide range of insults, and bound IgM activates the complement cascade. Once this injurious immune process starts, it generates additional neoepitopes for natural IgM, perpetuating the renal injury even if the primary disease process ceases. To test this hypothesis, the following specific aims will be pursued. 1) Test whether natural IgM causes progressive glomerulosclerosis. In this aim we will test whether mice deficient in soluble IgM are protected from CKD progression in two animal models, and we will test the ability of specific monoclonal IgM antibodies to restore injury. 2) Investigate the mechanisms of complement-mediated glomerular injury. The hypothesis for this aim is that C3a and C5a are generated in the glomeruli of subjects with CKD and promote glomerulosclerosis. We will examine the effects of these complement activation fragments on the different glomerular cell types in vitro and in vivo. 3) Develop novel therapies for the treatment of progressive CKD. The hypothesis for this aim is that a novel complement inhibitor that specifically targets injury-associated glomerular epitopes will slow the progression of renal disease. The experiments in this proposal will advance our understanding of the pathogenesis of CKD and foster the development of improved immunomodulatory treatments for this disease.
NIH ExPorter
NIH ExPorter