Membranoproliferative glomerulonephritis type II or Dense Deposit Disease (MPGNII/DDD) is characterized by the deposition of electron-dense material within the glomerular basement membrane (GBM) of the kidney and within Bruch's membrane in the eye. The diagnosis is usually made in children between the ages of 5-15 years. Within 10 years about half of these children progress to end-stage renal disease, occasionally with the late comorbidity of visual impairment. In most persons with MPGNII/DDD, hypocomplementemia due to continuous C3 degradation can be documented in plasma by low APH 50 values, low Cs levels, and the appearance of the Cs degradation product Csd. Renal transplantation is associated with disease recurrence in virtually all allografts and a high percentage of transplants ultimately fail. MPGNII/DDD is a complex disease. We hypothesize that: i) its pathophysiology is related to dysregulation of the alternative pathway (AP) C3 convertase, which leads to uncontrolled activation of the AP of complement; 2) uncontrolled activation of the AP of complement occurs on a permissive genetic background; and 3) damage to the GBM and Bruch's membrane occurs because these two membranes have only marginal protection from AP-mediated complement injury. We provide preliminary evidence to support this hypothesis by showing that specific mutations and/or alleles of Factor H, Factor H-Related 5 and Cs are associated with MPGNII/DDD. For two of the Factor H-associated alleles, the AK224 and H402, we have completed functional studies that demonstrate differences in the mutant proteins as compared to wild type protein. In this grant we will complete three specific aims to investigate in greater detail the role of the AP of complement in MPGNII/DDD.
The specific aims are: 1.
Specific Aim i : To examine the hypothesis that alleles/mutations in several complement-related genes are associated with MPGNII/DDD 2.
Specific Aim 2 : To examine the hypothesis that the associated alleles/mutations identified in Specific Aim ! affect the AP of complement at a functional level 3.
Specific Aim 3 : To examine the hypothesis that exogenous murine Factor H (mFH) can rescue the MPGNII/DDD phenotype in the Factor H deficient mouse (C/ft-/-) ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK074409-01A2
Application #
7313654
Study Section
Pathobiology of Kidney Disease Study Section (PBKD)
Program Officer
Flessner, Michael Francis
Project Start
2007-09-20
Project End
2012-06-30
Budget Start
2007-09-20
Budget End
2008-06-30
Support Year
1
Fiscal Year
2007
Total Cost
$278,590
Indirect Cost
Name
University of Iowa
Department
Otolaryngology
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Zhang, Yuzhou; Nester, Carla M; Holanda, Danniele G et al. (2013) Soluble CR1 therapy improves complement regulation in C3 glomerulopathy. J Am Soc Nephrol 24:1820-9
Sethi, Sanjeev; Fervenza, Fernando C; Zhang, Yuzhou et al. (2013) Atypical postinfectious glomerulonephritis is associated with abnormalities in the alternative pathway of complement. Kidney Int 83:293-9
Zand, Ladan; Kattah, Andrea; Fervenza, Fernando C et al. (2013) C3 glomerulonephritis associated with monoclonal gammopathy: a case series. Am J Kidney Dis 62:506-14
Eyler, Stephen J; Meyer, Nicole C; Zhang, Yuzhou et al. (2013) A novel hybrid CFHR1/CFH gene causes atypical hemolytic uremic syndrome. Pediatr Nephrol 28:2221-5
Gurkan, Sevgi; Fyfe, Billie; Weiss, Lynne et al. (2013) Eculizumab and recurrent C3 glomerulonephritis. Pediatr Nephrol 28:1975-81
Nester, Carla M; Smith, Richard J (2013) Treatment options for C3 glomerulopathy. Curr Opin Nephrol Hypertens 22:231-7
Sethi, Sanjeev; Fervenza, Fernando C; Zhang, Yuzhou et al. (2012) Secondary focal and segmental glomerulosclerosis associated with single-nucleotide polymorphisms in the genes encoding complement factor H and C3. Am J Kidney Dis 60:316-21
Sethi, Sanjeev; Nester, Carla M; Smith, Richard J H (2012) Membranoproliferative glomerulonephritis and C3 glomerulopathy: resolving the confusion. Kidney Int 81:434-41
Sethi, Sanjeev; Fervenza, Fernando C; Zhang, Yuzhou et al. (2012) C3 glomerulonephritis: clinicopathological findings, complement abnormalities, glomerular proteomic profile, treatment, and follow-up. Kidney Int 82:465-73
Lu, Der-Fa; Moon, Mikyung; Lanning, Lynne D et al. (2012) Clinical features and outcomes of 98 children and adults with dense deposit disease. Pediatr Nephrol 27:773-81

Showing the most recent 10 out of 23 publications