Focal and segmental glomerulosclerosis induced in mice lacking decay-accelerating factor in T cells
Lihua Bao, … , Stuart J. Shankland, Richard J. Quigg
Lihua Bao, … , Stuart J. Shankland, Richard J. Quigg
Published April 1, 2009
Citation Information: J Clin Invest. 2009;119(5):1264-1274. https://doi.org/10.1172/JCI36000.
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Focal and segmental glomerulosclerosis induced in mice lacking decay-accelerating factor in T cells

Abstract

Heritable and acquired diseases of podocytes can result in focal and segmental glomerulosclerosis (FSGS). We modeled FSGS by passively transferring mouse podocyte–specific sheep Abs into BALB/c mice. BALB/c mice deficient in the key complement regulator, decay-accelerating factor (DAF), but not WT or CD59-deficient BALB/c mice developed histological and ultrastructural features of FSGS, marked albuminuria, periglomerular monocytic and T cell inflammation, and enhanced T cell reactivity to sheep IgG. All of these findings, which are characteristic of FSGS, were substantially reduced by depleting CD4+ T cells from Daf–/– mice. Furthermore, WT kidneys transplanted into Daf–/– recipients and kidneys of DAF-sufficient but T cell–deficient Balb/cnu/nu mice reconstituted with Daf–/– T cells developed FSGS. In contrast, DAF-deficient kidneys in WT hosts and Balb/cnu/nu mice reconstituted with DAF-sufficient T cells did not develop FSGS. Thus, we have described what we believe to be a novel mouse model of FSGS attributable to DAF-deficient T cell immune responses. These findings add to growing evidence that complement-derived signals shape T cell responses, since T cells that recognize sheep Abs bound to podocytes can lead to cellular injury and development of FSGS.

Authors

Lihua Bao, Mark Haas, Jeffrey Pippin, Ying Wang, Takashi Miwa, Anthony Chang, Andrew W. Minto, Miglena Petkova, Guilin Qiao, Wen-Chao Song, Charles E. Alpers, Jian Zhang, Stuart J. Shankland, Richard J. Quigg

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Figure 4

Susceptibility to anti-podo Ab–induced FSGS occurs when DAF is absent from T cells.

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Susceptibility to anti-podo Ab–induced FSGS occurs when DAF is absent fr...
(A) Shown are urinary albumin excretion (left) and the extent of glomerulosclerosis (right) 30 days after administration of anti-podo Abs in individual Daf–/– mice depleted of CD4+ cells, with mAb GK1.5 or controls receiving irrelevant rat IgG2b. All data were normally distributed (Anderson-Darling test; P > 0.05) and compared by t testing, with P values provided above the data. (B) Infiltration with Thy-1.2+ T cells (brown, arrow) and F4/80+ monocytic cells (purple, arrow) was significantly reduced 30 days after administration of anti-podo Abs in CD4+ cell–depleted but not control Daf–/– mice. (C) Balb/cnu/nu mice reconstituted with DAF-deficient but not WT T cells developed albuminuria and FSGS. Urinary albumin excretion (left) and the percentage of segmentally sclerotic glomeruli (right) in individual Balb/cnu/nu mice that received T cells from WT (blue symbols) or Daf–/– mice (red symbols) 30 days after administration of anti-podo Abs. Experiments differed by whether mice were reconstituted with partially (diamonds) or highly (circles) purified T cells. All data sets in mice receiving T cells from Daf–/– mice were normally distributed with no differences comparing partially and highly purified T cells. Means and 95% CIs for the combined groups are shown as horizontal bars and open boxes, respectively. (D) Representative PAS-stained kidney sections from individual mice show the presence of segmental sclerosis (arrow) only in mice with DAF-deficient T cells. Original magnification, ×600.