C3 is central to the interstitial component of experimental immune complex glomerulonephritis

Welch, Thomas R.; Blystone, Lisa W.

doi:10.1016/j.clim.2004.10.008

Cited by 6 publications

(11 citation statements)

References 14 publications

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“…Furthermore, there was no difference among groups in proteinuria or renal function. The glomerular histology in these animals did not differ from our previously published observations in untransplanted animals [7].…”

Section: Discussionsupporting

confidence: 57%

“…A series of digital images representing the complete cortex from a periodic acid-Schiff-stained kidney section from each animal was collected with a SPOT Diagnostics camera (Sterling Heights, MI), as we have previously described [7]. These images were then analyzed for the following measures:…”

Section: Methodsmentioning

confidence: 99%

“…Although we have reported several studies addressing the role of locally synthesized complement by tubular epithelium in the renal interstitium [1]–[3], [7], the role of monocyte-derived complement in the glomerulus has not been addressed. In the experiments reported herein, we employ a novel strategy by which animals deficient in C3 undergo hematologic reconstitution with bone marrow from C3 replete animals.…”

Section: Introductionmentioning

confidence: 99%

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Immune Complex Glomerulonephritis Following Bone Marrow Transplantation in C3 Deficient Mice

Welch

Blystone

2008

PLoS ONE

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BackgroundThe role of circulating complement in host defense and immune disease is well established. Although a number of cells and tissues are capable of synthesizing complement components locally, the importance of such local synthesis in immune disease has been difficult to establish.Methodology/Principal FindingsWe used bone marrow transplantation (BMT) between C3 knockout (C3KO) and wild type (WT) mice to construct animals that were discordant for systemic (hepatic) and local (monocytic) C3 synthetic capacity. An immune complex glomerulonephritis (GN) was then induced using intraperitoneal injections of horse spleen apoferritin (HSA) with a lipopolysaccharide (LPS) adjuvant. All HSA/LPS animals developed a proliferative GN with glomerular infiltration by monocytes. By sensitive ELISA, monocyte C3 synthesis could be detected in C3KO animals transplanted with WT bone marrow cells. Despite this, there were no significant differences among groups of mice in measures of clinical (proteinuria, renal function) or histologic (glomerular cellularity, crescents) disease severity.Conclusions/SignificanceIn this model of GN, local synthesis of C3 by infiltrating cells does not appear to be of pathologic importance.

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Section: Discussionsupporting

confidence: 57%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Immune Complex Glomerulonephritis Following Bone Marrow Transplantation in C3 Deficient Mice

Welch

Blystone

2008

PLoS ONE

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“…25,33 C3 of proximal tubule cell origin is a crucial mediator of injury in experimental acute allograft rejection and after renal ischemia and reperfusion. 23,34 Its expression was enhanced in both human and experimental proteinuric nephropathies.…”

Section: Discussionmentioning

confidence: 99%

Complement-Mediated Dysfunction of Glomerular Filtration Barrier Accelerates Progressive Renal Injury

Abbate

Zoja

Corna

et al. 2008

Journal of the American Society of Nephrology

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Intrarenal complement activation leads to chronic tubulointerstitial injury in animal models of proteinuric nephropathies, making this process a potential target for therapy. This study investigated whether a C3-mediated pathway promotes renal injury in the protein overload model and whether the abnormal exposure of proximal tubular cells to filtered complement could trigger the resulting inflammatory response. Mice with C3 deficiency were protected to a significant degree against the protein overload-induced interstitial inflammatory response and tissue damage, and they had less severe podocyte injury and less proteinuria. When the same injury was induced in wild-type (WT) mice, antiproteinuric treatment with the angiotensin-converting enzyme inhibitor lisinopril reduced the amount of plasma protein filtered, decreased the accumulation of C3 by proximal tubular cells, and protected against interstitial inflammation and damage. For determination of the injurious role of plasma-derived C3, as opposed to tubular cell-derived C3, C3-deficient kidneys were transplanted into WT mice. Protein overload led to the development of glomerular injury, accumulation of C3 in podocytes and proximal tubules, and tubulointerstitial changes. Conversely, when WT kidneys were transplanted into C3-deficient mice, protein overload led to a more mild disease and abnormal C3 deposition was not observed. These data suggest that the presence of C3 increases the glomerular filtration barrier's susceptibility to injury, ultrafiltered C3 contributes more to tubulointerstitial damage induced by protein overload than locally synthesized C3, and local C3 synthesis is irrelevant to the development of proteinuria. It is speculated that therapies targeting complement combined with interventions to minimize proteinuria would more effectively prevent the progression of renal disease.

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“…Complement present within the ICs can function as a mediator linking antibody deposition with glomerular dysfunction and tissue injury, but can also influence glomerular handling of IC by changing its physiochemical characteristics [28,29]. Previous work using LPS/HSA-treated complement C3-, C4-and C5-deficient mice showed no apparent difference in glomerular injury when compared to wild-type mice, but a mechanism was described as to how a primary glomerular process could progress to involve the tubulo-interstitial compartment in a complement-dependent manner [12][13][14]30,31]. In the initial phase of GN, the complement source is the circulation as the amount of complement mRNA detected in healthy kidney, with the exception of C4, is low.…”

Section: Discussionmentioning

confidence: 99%

Shift of C3 deposition from localization in the glomerulus into the tubulo-interstitial compartment in the absence of secreted IgM in immune complex glomerulonephritis

Vaculik¹,

Rüger²,

Yanagida³

et al. 2007

Clinical and Experimental Immunology

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SummaryThe role of secretory IgM in protecting kidney tissue from immune complex glomerulonephritis induced by 4 mg horse spleen apoferritin and 0·05 mg lipopolysaccharide has been investigated in mutant mice in which B cells do not secrete IgM, but are capable of expressing surface IgM and IgD and secreting other Ig isotypes. Glomerular size, number of glomeruli per crosssection, glomerular cellularity and urine content of protein and creatinine was comparable in treated secreted IgM (sIgM)-deficient and wild-type mice. Assessment of urinary proteins by sodium dodecyl sulphate-polyacrylamide gel electrophoresis showed a 30 kDa low molecular weight protein in treated sIgM-deficient animals only, reflecting dysfunction of proximal tubules. A shift of bound C3 from glomeruli to the tubulo-interstitial compartment in sIgM-deficient mice also suggests tubulo-interstitial damage. In contrast, local C3 synthesis within the kidney tissue did not differ between the two treated groups. Apoptosis physiologically present to maintain kidney cell homeostasis was increased slightly in treated wild-type mice. These results indicate that secretory IgM can protect the tubulo-interstitial compartment from immune complex-induced damage without having an effect on the glomerulus.

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C3 is central to the interstitial component of experimental immune complex glomerulonephritis

Cited by 6 publications

References 14 publications

Immune Complex Glomerulonephritis Following Bone Marrow Transplantation in C3 Deficient Mice

Immune Complex Glomerulonephritis Following Bone Marrow Transplantation in C3 Deficient Mice

Complement-Mediated Dysfunction of Glomerular Filtration Barrier Accelerates Progressive Renal Injury

Shift of C3 deposition from localization in the glomerulus into the tubulo-interstitial compartment in the absence of secreted IgM in immune complex glomerulonephritis

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