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Abrogation of immune complex glomerulonephritis by native carboxypeptidase and pharmacological antagonism of the C5a receptor

View Article: PubMed Central - PubMed

ABSTRACT

Activation of complement generates C5a which leads to signaling through C5aR1. This is tightly controlled, including by the plasma proteins factor H (FH) and carboxypeptidase N. Here we studied a chronic serum sickness (CSS) model of glomerulonephritis (GN) in which there is an active humoral immune response, formation of glomerular immune complexes (ICs), and resulting glomerular inflammation. The antibody response, glomerular IC deposition, the degree of GN, and consequent renal functional insufficiency in CSS were all worse in FH−/− mice compared to wild-type FH+/+ animals. This was ameliorated in the former by giving a C5aR1 antagonist for the final 3 weeks of the 5-week protocol. In contrast, blocking CP-mediated inactivation of C5a increased these disease measures. Thus, complement regulation by both plasma FH and CP to limit the quantity of active C5a is important in conditions where the humoral immune response is directed to a continuously present foreign antigen. Signaling through C5aR1 enhances the humoral immune response as well as the inflammatory response to ICs that have formed in glomeruli. Both effects are relevant even after disease has begun. Thus, pharmacological targeting of C5a in IC-mediated GN has potential clinical relevance.

No MeSH data available.


Related in: MedlinePlus

C5a-dependent renal functional impairment in wild-type mice with CSS. CSS was induced in wild-type (FH+/+) mice by daily immunization with apoferritin, or saline alone as control. One group also received CPinh after 3 weeks. Shown are individual BUN values from all mice studied after 5 weeks. Data from each group were normally distributed. The horizontal lines are the mean value in each group. Groups were significantly different by ANOVA (P < 0.001). Between-group comparisons are depicted in the Figure.
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fig3: C5a-dependent renal functional impairment in wild-type mice with CSS. CSS was induced in wild-type (FH+/+) mice by daily immunization with apoferritin, or saline alone as control. One group also received CPinh after 3 weeks. Shown are individual BUN values from all mice studied after 5 weeks. Data from each group were normally distributed. The horizontal lines are the mean value in each group. Groups were significantly different by ANOVA (P < 0.001). Between-group comparisons are depicted in the Figure.

Mentions: It appears when plasma FH is absent in FH−/− mice with CSS, there is sufficient productive generation of C5a to signal through C5aR119. Given the effects of CPinh on FH−/− mice with CSS, we investigated whether it would affect CSS in wild-type (i.e., FH+/+) mice. All control wild-type mice given saline instead of apoferritin (n = 8) had normal BUN values (<29.0 mg/dl) and no histopathological evidence of GN. Of the mice with CSS, 3 of 5 developed mild GN (score = 0.5) which was reflected by elevated BUN values (31.5–33.5 mg/dl). The mice with CSS also given CPinh had a small, but consistent increase in GN, with all five animals having GN scores 0.5–1.0 and BUN values ≥33.5 mg/dl (Figure 3). As with FH−/− mice with CSS, GN scores and BUN values were strongly correlated (BUN = 26.7 + (13.1 × GN); r = 0.75, P < 0.001), supporting the relevance and interrelatedness of these two measures. These data further support the importance of both FH and CP to limit C5a generation in pathological states of IC deposition.


Abrogation of immune complex glomerulonephritis by native carboxypeptidase and pharmacological antagonism of the C5a receptor
C5a-dependent renal functional impairment in wild-type mice with CSS. CSS was induced in wild-type (FH+/+) mice by daily immunization with apoferritin, or saline alone as control. One group also received CPinh after 3 weeks. Shown are individual BUN values from all mice studied after 5 weeks. Data from each group were normally distributed. The horizontal lines are the mean value in each group. Groups were significantly different by ANOVA (P < 0.001). Between-group comparisons are depicted in the Figure.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5037280&req=5

fig3: C5a-dependent renal functional impairment in wild-type mice with CSS. CSS was induced in wild-type (FH+/+) mice by daily immunization with apoferritin, or saline alone as control. One group also received CPinh after 3 weeks. Shown are individual BUN values from all mice studied after 5 weeks. Data from each group were normally distributed. The horizontal lines are the mean value in each group. Groups were significantly different by ANOVA (P < 0.001). Between-group comparisons are depicted in the Figure.
Mentions: It appears when plasma FH is absent in FH−/− mice with CSS, there is sufficient productive generation of C5a to signal through C5aR119. Given the effects of CPinh on FH−/− mice with CSS, we investigated whether it would affect CSS in wild-type (i.e., FH+/+) mice. All control wild-type mice given saline instead of apoferritin (n = 8) had normal BUN values (<29.0 mg/dl) and no histopathological evidence of GN. Of the mice with CSS, 3 of 5 developed mild GN (score = 0.5) which was reflected by elevated BUN values (31.5–33.5 mg/dl). The mice with CSS also given CPinh had a small, but consistent increase in GN, with all five animals having GN scores 0.5–1.0 and BUN values ≥33.5 mg/dl (Figure 3). As with FH−/− mice with CSS, GN scores and BUN values were strongly correlated (BUN = 26.7 + (13.1 × GN); r = 0.75, P < 0.001), supporting the relevance and interrelatedness of these two measures. These data further support the importance of both FH and CP to limit C5a generation in pathological states of IC deposition.

View Article: PubMed Central - PubMed

ABSTRACT

Activation of complement generates C5a which leads to signaling through C5aR1. This is tightly controlled, including by the plasma proteins factor H (FH) and carboxypeptidase N. Here we studied a chronic serum sickness (CSS) model of glomerulonephritis (GN) in which there is an active humoral immune response, formation of glomerular immune complexes (ICs), and resulting glomerular inflammation. The antibody response, glomerular IC deposition, the degree of GN, and consequent renal functional insufficiency in CSS were all worse in FH&minus;/&minus; mice compared to wild-type FH+/+ animals. This was ameliorated in the former by giving a C5aR1 antagonist for the final 3 weeks of the 5-week protocol. In contrast, blocking CP-mediated inactivation of C5a increased these disease measures. Thus, complement regulation by both plasma FH and CP to limit the quantity of active C5a is important in conditions where the humoral immune response is directed to a continuously present foreign antigen. Signaling through C5aR1 enhances the humoral immune response as well as the inflammatory response to ICs that have formed in glomeruli. Both effects are relevant even after disease has begun. Thus, pharmacological targeting of C5a in IC-mediated GN has potential clinical relevance.

No MeSH data available.


Related in: MedlinePlus