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GG-13 Pathogenesis of lupus proliferative glomerulonephritis (LPGN): podocytes as targets and responders provide evidence for the importance of local factors controlling end organ damage
  1. Shu Man Fu1,
  2. Hongyang Wang1,
  3. Chao Dai1,
  4. Sun-sang J Sung1 and
  5. Felicia Gaskin2
  1. 1Division of Rheumatology and Immunology, the Centre of Inflammation, Immunity and Regenerative Medicine and Division of Nephrology, Department of Medicine, University of Virginia, Charlottesville, VA, USA
  2. 2Department of Psychiatry and Neurobehavioral Sciences University of Virginia, Charlottesville, VA, USA


Background LPGN is the prototypic immune-complex (IC) mediated disease. The current dogma that IC deposition with complement (C’) activation inevitably leads to renal damage is neither sufficient nor comprehensive to account for the pathogenesis of LPGN. Our genetic studies support the thesis that acute GN (aGN) with IC deposition with C’ activation and cell infiltration and mesangial proliferation is a distinct phenotype from chronic GN (cGN) that is characterised by glomerulosclerosis, tubular dilatation and interstitial fibrosis with severe proteinuria and premature mortality. Furthermore, circulating ANA and anti-dsDNA Abs are not required for LPGN.

Materials and methods Female mice of NZM2328 and its intra-chromosomal recombinant congenic line NZM2328.Lc1R27 (R27) were used. Anti-GBM induced GN was used as a model for IC mediated LPGN. Immunofluorescence was used to identify cell populations that made cytokines and complement components.

Results R27 developed aGN and mild proteinuria without progression to cGN, end stage renal failure and early mortality. The kidneys of aged R27 had IC deposition and cellular infiltration, not distinguishable from that of aGN in NZM2328. Multiple approaches showed that the lack of progression from aGN to cGN in R27 was due to podocyte resistance to IC-mediated damage, a phenotype controlled by the allelic Cgnz1 gene.

With a novel method to study intra-glomerular cytokine production, NZM podocytes were shown to be the major cell population that makes IL-1β in cGN, infiltrating CD11b+ macrophages make TNFα and the mesangial cells make IL-6. R27 mice do not show this compartmentalization of cytokine production. Preliminary data showed that the podocytes in Class III and IV lupus GN make IL-1β.

Podocytes at the early and late cGN were shown to make C1q and C3. The expression of these complement components is less evident in R27 kidneys. C1q and C3 were present in some podocytes in biopsies of class III and IV lupus nephritis. Urinary podocytes making C1q were detected by us in of four patients with LPGN but not in normal individuals.

Conclusions Our studies of lupus GN in both mouse and in man have provided significant information and insight regarding the role of podocytes as targets and as responders to IC mediated injuries. Our results suggest that the pathogenesis of LPGN should be revisited with focus on the local factors that may be of paramount importance. In addition to enhance our basic knowledge of podocyte biology, our results may provide novel targets for intervention and new urinary biomarkers to monitor therapeutic responses.

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