Complement and the Kidney

Quigg, Richard J.

doi:10.4049/jimmunol.171.7.3319

Cited by 46 publications

(36 citation statements)

References 94 publications

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“…26,[28][29][30][31] As the activating proteins in the complement systems of humans and mice are largely comparable, their study in mice can provide useful insights into human pathophysiology. 32 The complement regulators in mice are also largely conserved in humans with some notable differences. In mice, there are two forms of DAF (DAF1 and DAF2) encoded on chromosome 1 33 and CD59 (CD59a and CD59b) encoded on chromosome 2; 34 DAF1 and CD59a have 85% nucleotide identity to their respective alternate forms.…”

Section: Discussionmentioning

confidence: 99%

Decay-accelerating factor but not CD59 limits experimental immune-complex glomerulonephritis

Bao

Haas

Minto

et al. 2007

Laboratory Investigation

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The complex balance between the pro-activating and regulatory influences of the complement system can affect the pathogenesis of immune complex-mediated glomerulonephritis (ICGN). Key complement regulatory proteins include decay accelerating factor (DAF) and CD59, which inhibit C3 activation and C5b-9 generation, respectively. Both are glycosylphosphatidylinositol-linked cell membrane proteins, which are widely distributed in humans and mice. Chronic serum sickness induced by daily immunization with horse spleen apoferritin over 6 weeks was used to induce ICGN in DAF-, CD59-and DAF/CD59-deficient mice, with wild-type littermate mice serving as controls. Both DAF and DAF/CD59-deficient mice had an increased incidence of GN relative to wild-type controls associated with significantly increased glomerular C3 deposition. Disease expression in CD59-deficient mice was no different than wild-type controls. DAF-and DAF/CD59-deficient mice also had increased monocyte chemoattractant protein-1 mRNA expression and glomerular infiltration with CD45 þ leukocytes. Our findings suggest that activation of C3 is strongly associated with experimental ICGN while downstream formation of C5b-9 is of lesser pathogenic importance in this model.

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Section: Discussionmentioning

confidence: 99%

Decay-accelerating factor but not CD59 limits experimental immune-complex glomerulonephritis

Bao

Haas

Minto

et al. 2007

Laboratory Investigation

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“…Efforts to interrupt the activation of complement have thus far not been successful in ameliorating the MPGN of TSLP transgenic mice (41), although such measures have been successful in other models of glomerulonephritis (34,36). A very recent and potentially important finding is the demonstration of upregulated expression of the Toll-like receptor 3 in human HCV-associated MPGN (42).…”

Section: Hepatitis C Virus-associated Glomerulonephritismentioning

confidence: 99%

Emerging Paradigms in the Renal Pathology of Viral Diseases

Alpers¹,

Kowalewska²

2007

Clinical Journal of the American Society of Nephrology

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This review considers recent information that illuminates pathogenetic mechanisms that involve three of the major viral infections that cause renal injury in the form of HIV-associated nephropathy, polyoma virus nephropathy, and hepatitis C virus-associated glomerulonephritis.Clin J Am Soc Nephrol 2: S6 -S12, 2007. doi: 10.2215/CJN.00280107 HIV-Associated NephropathyA nephropathy that is associated with HIV infection was identified soon after the epidemic of HIV/AIDS first became recognized in the early 1980s. HIV-associated nephropathy (HIVAN) is a combined glomerular and tubular injury that is characterized by a collapsing glomerulopathy (CG) with collapse of glomerular capillary structures and a striking hyperplasia of podocytes, microcystic transformation of renal tubules, and concomitant and likely nonspecific interstitial inflammation and fibrosis consequent to the glomerular and tubular injuries (Figure 1). From a pathology standpoint, three major areas of investigation have led to a deeper understanding of this lesion.The first of these addresses the issue of whether HIVAN is a direct consequence of viral infection of the renal parenchyma or is a secondary consequence of systemic infection. Cohen et al.(1) first reported the presence of HIV RNA in podocytes as revealed by in situ hybridization (ISH) in 1989, a finding that was supported by microdissection studies of Kimmel et al. (2). These studies were difficult to validate because of the failure of others to replicate these findings using conventional techniques of ISH, the inability to demonstrate the presence of viral peptides in renal parenchymal cells by immunohistochemistry, and the inability to demonstrate appropriate receptors for viral entry into cells, namely CD4 and the chemokine receptors CXCR4 or CCR5, on renal parenchymal cells (3). This created a conundrum in that a mechanism for viral entry into renal cells could not be defined. Some but not all of the difficulties were resolved by a more sophisticated form of ISH, which is based on a technique that detects forms of viral DNA that are characteristic of replicating virus (4 -6). With these techniques, it was possible to substantiate the findings of Cohen et al. and convincingly demonstrate HIV infection of podocytes and tubular epithelial cells.A second key development concomitant with the demonstration of HIV infection of human renal epithelial cells was the development of murine models of HIVAN. The best studied of these involves the Tg26 mouse: Mice are made transgenic for a nearly whole-length HIV virus but with a deletion of HIV gag and pol genes to render the virus nonreplicative (7). Studies of these mice, largely by the group of Klotman and their collaborators, have established that expression of HIV genes, presumably modeling the events of renal HIV infection, is sufficient to produce a renal injury in the mouse that is similar to HIVAN in humans. Studies in which kidneys from transgenic mice were transplanted into wild-type controls demonstrated that renal expression of HIV gene...

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“…Complement activation is intimately involved in the metabolism of immune complexes by limiting their size and interaction with receptors responsible for their clearance (46,106). By virtue of its physicochemical characteristics, actively administered cationized bovine serum albumin becomes incorporated into subepithelial immune complexes, leading to a model of MN in which disease expression is dependent on generation of C5b-9 on the podocyte (45).…”

Section: Other Effects Of Complement In Experimental Mnmentioning

confidence: 99%

Experimental membranous nephropathy redux

Cybulsky

Quigg²,

Salant³

2005

American Journal of Physiology-Renal Physiology

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117

133

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Membranous nephropathy (MN) is a common cause of nephrotic syndrome in adults. Active and passive Heymann nephritis (HN) in rats are valuable experimental models because their features so closely resemble human MN. In HN, subepithelial immune deposits form in situ as a result of circulating antibodies. Complement activation leads to assembly of C5b-9 on glomerular epithelial cell (GEC) plasma membranes and is essential for sublethal GEC injury and the onset of proteinuria. This review revisits HN and focuses on areas of substantial progress in recent years. The response of the GEC to sublethal C5b-9 attack is not simply due to disruption of the plasma membrane but is due to the activation of specific signaling pathways. These include activation of protein kinases, phospholipases, cyclooxygenases, transcription factors, growth factors, NADPH oxidase, stress proteins, proteinases, and others. Ultimately, these signals impact on cell metabolic pathways and the structure/function of lipids and key proteins in the cytoskeleton and slit-diaphragm. Some signals affect GEC adversely. Thus C5b-9 induces partial dissolution of the actin cytoskeleton. There is a decline in nephrin expression, reduction in F-actin-bound nephrin, and loss of slit-diaphragm integrity. Other signals, such as endoplasmic reticulum stress, may limit complement-induced injury, or promote recovery. The extent of complement activation and GEC injury is dependent, in part, on complement-regulatory proteins, which act at early or late steps within the complement cascade. Identification of key steps in complement activation, the cellular signaling pathways, and the targets will facilitate therapeutic intervention in reversing GEC injury in human MN.

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Complement and the Kidney

Cited by 46 publications

References 94 publications

Decay-accelerating factor but not CD59 limits experimental immune-complex glomerulonephritis

Decay-accelerating factor but not CD59 limits experimental immune-complex glomerulonephritis

Emerging Paradigms in the Renal Pathology of Viral Diseases

Experimental membranous nephropathy redux

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