Chronic Progression of Tubulointerstitial Damage in Proteinuric Renal Disease Is Mediated by Complement Activation

Hsu, Stephen I‐Hong; Couser, William G.

doi:10.1097/01.asn.0000070032.58017.20

Cited by 77 publications

(74 citation statements)

References 65 publications

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“…High-expression MBL genotypes occurred with increased frequency among patients with nephropathy, and although the odds ratio was relatively small, this seems to indicate that inherited high concentrations of circulating MBL may be a risk factor for diabetic nephropathy. Mounting evidence suggests that there may be a link between complement activation and the development of diabetic renal complications (25,26), and MBL-mediated complement activation has recently been implicated in the pathogenesis of other renal diseases, such as IgA nephropathy and Henoch-Schonlein purpura nephritis (27,28). It could thus be hypothesized that in diabetic patients, high levels of MBL may contribute to the development of nephropathy through aggravated complement activation.…”

Section: Discussionmentioning

confidence: 99%

Association Between Mannose-Binding Lectin and Vascular Complications in Type 1 Diabetes

et al. 2004

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Complement activation and inflammation have been suggested in the pathogenesis of diabetic vascular lesions. We investigated serum mannose-binding lectin (MBL) levels and polymorphisms in the MBL gene in type 1 diabetic patients with and without diabetic nephropathy and associated macrovascular complications. Polymorphisms in the MBL gene and serum MBL levels were determined in 199 type 1 diabetic patients with overt nephropathy and 192 type 1 diabetic patients with persistent normoalbuminuria matched for age, sex, and duration of diabetes, as well as in 100 healthy control subjects. The frequencies of high-and low-expression MBL genotypes were similar in patients with type 1 diabetic and healthy control subjects. High MBL genotypes were significantly more frequent in diabetic patients with nephropathy than in the normoalbuminuric group, and the risk of having nephropathy given a high MBL genotype assessed by odds ratio (OR) was 1.52 (1.02-2.27, P ‫؍‬ 0.04). Median serum MBL concentrations were significantly higher in patients with nephropathy than in patients with normoalbuminuria: 2,306 g/l (interquartile range [IQR] 753-4,867 g/l) vs. 1,491 g/l (577-2,944 g/l), P ‫؍‬ 0.0003. In addition, even when comparing patients with identical genotypes, serum MBL levels were higher in the nephropathy group than in the normoalbuminuric group. Patients with a history of cardiovascular disease had significantly elevated MBL levels independent of nephropathy status (3,178 g/l [IQR 636 -5,231 g/l] vs. 1,741 g/l [656 -3,149 g/l], P ‫؍‬ 0.02). The differences in MBL levels between patients with and without vascular complications were driven primarily by pronounced differences among carriers of high MBL genotypes (P < 0.0001). Our findings suggest that MBL may be involved in the pathogenesis of micro-and macrovascular complications in type 1 diabetes, and that determination of MBL status might be used to identify patients at increased risk of developing these complications. Diabetes 53

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Section: Discussionmentioning

confidence: 99%

Association Between Mannose-Binding Lectin and Vascular Complications in Type 1 Diabetes

et al. 2004

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“…Finally, it appears that complement proteins present in the glomerular ultrafiltrate in proteinuric diseases such as MN can be activated via the alternative pathway and lead to C5b-9 generation on tubular epithelium (8,90). As reviewed in detail elsewhere, it is conceivable that such tubular damage from complement activation is responsible for progressive interstitial inflammation and fibrosis (52).…”

Section: Other Effects Of Complement In Experimental Mnmentioning

confidence: 99%

Experimental membranous nephropathy redux

Cybulsky

Quigg²,

Salant³

2005

American Journal of Physiology-Renal Physiology

116

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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“…9 C3 and other complement proteins were found in proximal tubules in human renal biopsy material 10,11 and in kidneys of rats after extensive renal mass reduction [12][13][14] or other proteinuric models. 13,[15][16][17] Protective effects of limiting complement activation were revealed using C6-deficient animals 16,17 or genetically modified mice overexpressing a soluble C3 inhibitor 18 and by pharmacologic manipulations.…”

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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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Chronic Progression of Tubulointerstitial Damage in Proteinuric Renal Disease Is Mediated by Complement Activation

Cited by 77 publications

References 65 publications

Association Between Mannose-Binding Lectin and Vascular Complications in Type 1 Diabetes

Association Between Mannose-Binding Lectin and Vascular Complications in Type 1 Diabetes

Experimental membranous nephropathy redux

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

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