Urinary Biomarkers in Murine MPGN

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DESCRIPTION (provided by applicant): Membranoproliferative glomerulonephritis Type II (MPGN II) is an uncommon form of chronic renal disease primarily effecting older children and adolescents. It is defined histologically by the presence of electron dense deposits within the lamina densa of the glomerular basement membrane. While MPGN II is associated with both systemic hypocomplementemia and local deposition of complement components in the glomerulus, the pathogenic mechanisms that mediate renal injury in this disease remain undefined. Recently it has been demonstrated that mice deficient in Factor H, a critical regulator of the alternative complement pathway, develop chronic glomerular disease identical to that seen in humans with MPGN II. This proposal is designed to identify urinary biomarkers of renal injury in this model system. Using advanced proteomic tools, differential expression of urinary proteins will be analyzed comparing urine from mice deficient in Factor H to urine from control mice. Samples will be analyzed temporally to characterize progressive alterations in patterns of urinary protein expression. Proteins that are differentially expressed will then be characterized at multiple levels using immunohistochemically, Western Blot, and quantitative RT-PCR. The primary goals of this proposal are two fold, first to identify potential biomarkers specific for MPGN II, and second to gain insight into the pathogenic mechanisms by which complement activation mediates renal injury in a biologically relevant model of human disease. Findings from these studies have the potential to have a significant impact on our understanding of the basic mechanisms by which complement activation contributes to renal injury not only in MPGN II, but also in other complement dependent nephritidies including post-infectious glomerular nephritis and lupus nephritis.