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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 FH−/− mice with CSS. CSS was induced in FH−/− mice by daily immunization with apoferritin, or saline alone as control. Groups of animals also received C5aRant and/or CPinh after 2 and 3 weeks, respectively. 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). *P < 0.02 versus other three groups.
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fig1: C5a-dependent renal functional impairment in FH−/− mice with CSS. CSS was induced in FH−/− mice by daily immunization with apoferritin, or saline alone as control. Groups of animals also received C5aRant and/or CPinh after 2 and 3 weeks, respectively. 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). *P < 0.02 versus other three groups.

Mentions: As shown in Figure 1, control FH−/− mice had normal renal function at the end of the 5-week experimental protocol as assessed by BUN levels of 27.9 ± 1.1 mg/dl. In contrast, FH−/− mice with CSS induced by repetitive apoferritin immunization had impaired renal function (BUN = 37.0 ± 2.2 mg/dl). This was also true of those mice receiving CPant (BUN = 39.7 ± 2.8 mg/dl). Renal insufficiency was prevented in FH−/− mice receiving C5aR1ant for the final 3-week period, whether or not CPinh was administered (BUN = 26.0 ± 0.6 and 27.2 ± 2.1 mg/dl, respectively). Thus, functional renal insufficiency in the CSS model can be prevented after disease onset by pharmacological blockade of C5aR1.


Abrogation of immune complex glomerulonephritis by native carboxypeptidase and pharmacological antagonism of the C5a receptor
C5a-dependent renal functional impairment in FH−/− mice with CSS. CSS was induced in FH−/− mice by daily immunization with apoferritin, or saline alone as control. Groups of animals also received C5aRant and/or CPinh after 2 and 3 weeks, respectively. 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). *P < 0.02 versus other three groups.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig1: C5a-dependent renal functional impairment in FH−/− mice with CSS. CSS was induced in FH−/− mice by daily immunization with apoferritin, or saline alone as control. Groups of animals also received C5aRant and/or CPinh after 2 and 3 weeks, respectively. 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). *P < 0.02 versus other three groups.
Mentions: As shown in Figure 1, control FH−/− mice had normal renal function at the end of the 5-week experimental protocol as assessed by BUN levels of 27.9 ± 1.1 mg/dl. In contrast, FH−/− mice with CSS induced by repetitive apoferritin immunization had impaired renal function (BUN = 37.0 ± 2.2 mg/dl). This was also true of those mice receiving CPant (BUN = 39.7 ± 2.8 mg/dl). Renal insufficiency was prevented in FH−/− mice receiving C5aR1ant for the final 3-week period, whether or not CPinh was administered (BUN = 26.0 ± 0.6 and 27.2 ± 2.1 mg/dl, respectively). Thus, functional renal insufficiency in the CSS model can be prevented after disease onset by pharmacological blockade of C5aR1.

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