P-selectin deficiency exacerbates experimental glomerulonephritis: a protective role for endothelial P-selectin in inflammation

Rosenkranz, Alexander R.; Mendrick, Donna L.; Cotran, Ramzi S.; Mayadas, Tanya N.

doi:10.1172/jci5183

Cited by 117 publications

(128 citation statements)

References 47 publications

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“…Indeed, VCAM-1 has been suggested as a potential therapeutic target in end-organ disease (30,31), although antibody-mediated blocking in experimental immune nephritis has not been very effective (32). Likewise, it has been suggested that glomerular VCAM-1, P-SELECTIN, TNFRI, AND CXCL16 IN NEPHRITIC URINEdisease may be amenable to therapy by blocking P-selectin (16), although conflicting results have been noted in experimental immune nephritis (37). Based on the antibody-blocking studies described here, CXCL16 may turn out to be yet another therapeutic target in immune nephritis.…”

Section: Discussionmentioning

confidence: 88%

“…P-selectin is an adhesion molecule that is expressed on platelets and several other cell types, and the level of P-selectin has been reported to be elevated in other autoinflammatory diseases, in which it has also been recognized as a circulating disease marker (11)(12)(13). The prominence of P-selectin in experimentally induced immune nephritis has also been quite extensively studied (34)(35)(36)(37). Interestingly, a protective role for endothelial P-selectin in immune nephritis has been suggested (37).…”

Section: Discussionmentioning

confidence: 99%

“…The prominence of P-selectin in experimentally induced immune nephritis has also been quite extensively studied (34)(35)(36)(37). Interestingly, a protective role for endothelial P-selectin in immune nephritis has been suggested (37). It has also been observed to be expressed within the kidneys, in both mice and patients with spontaneous lupus nephritis (14,15).…”

Section: Discussionmentioning

confidence: 99%

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Excreted urinary mediators in an animal model of experimental immune nephritis with potential pathogenic significance

Xie

Bhaskarabhatla

et al. 2007

Arthritis & Rheumatism

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Objective. Currently, proteinuria is viewed as the earliest indicator of renal disease in immune-mediated nephritis. The objective of this study was to determine whether additional mediators may be excreted in the urine during immune-mediated nephritis, using an experimental model with a well-defined disease course.Methods. Urine samples from mice with antiglomerular basement membrane (anti-GBM) antibodyinduced experimental nephritis were screened using a focused immunoproteome array bearing 62 cytokines/ chemokines/soluble receptors. Molecules identified through this screening assay were validated using an enzyme-linked immunosorbent assay. One of these molecules was further evaluated for its pathogenic role in disease, using antibody-blocking studies.Results. Compared with B6 and BALB/c mice, in which moderately severe immune-mediated nephritis develops, the highly nephritis-susceptible 129/Sv and DBA/1 mice exhibited significantly increased urinary levels of vascular cell adhesion molecule 1 (VCAM-1), P-selectin, tumor necrosis factor receptor I (TNFRI), and CXCL16, particularly at the peak of disease. Whereas some of the mediators appeared to be serum derived early in the disease course, local production in the kidneys appeared to be an important source of these mediators later in the course of disease. Both intrinsic renal cells and infiltrating leukocytes appeared to be capable of producing these mediators. Finally, antibodymediated blocking of CXCL16 ameliorated experimental immune nephritis.Conclusion. These studies identified VCAM-1, P-selectin, TNFRI, and CXCL16 as a quartet of molecules that have potential pathogenic significance; the levels of these molecules are significantly elevated during experimental immune nephritis. The relevance of these molecules in spontaneous immune nephritis warrants investigation.

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Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Excreted urinary mediators in an animal model of experimental immune nephritis with potential pathogenic significance

Xie

Bhaskarabhatla

et al. 2007

Arthritis & Rheumatism

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“…20 Serum urea, serum calcium, and serum phosphate levels were measured with standard laboratory techniques. The glucose tolerance test was performed at the age of 7 weeks and the insulin tolerance test at the age of 15 weeks.…”

Section: Metabolic Studiesmentioning

confidence: 99%

A Murine Model of Phosphate Nephropathy

Eller

Kirsch

et al. 2011

The American Journal of Pathology

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We established a murine model of phosphate nephropathy with secondary hyperparathyroidism. db/db mice, which develop obesity and type 2 diabetes mellitus, were uninephrectomized at the age of 6 weeks and were fed either standard chow or a phosphorus-rich diet during the next 8 weeks. Thereafter, renal cryosections showed abundant tubular casts with a strong histochemical von Kossa reaction in all db/db mice on the phosphorus-rich diet but none in the controls. X-ray diffraction and Raman spectroscopy proved that these tubular casts consist mostly of hydroxyapatite Ca 5 (PO 4 ) 3 (OH). These intraluminal precipitations were located in distal tubuli and collecting ducts and were associated with degenerative tubular changes and peritubular infiltration of T cells and macrophages. In line, kidneys of db/db mice on the phosphorus-rich diet displayed significantly increased mRNA expression of the T H 1 cytokines interferon ␥, IL-6, and tumor necrosis factor ␣. In addition, mice developed signs of secondary hyperparathyroidism as shown by elevated serum phosphate, decreased serum calcium, and increased parathyroid hormone, osteopontin, and fibroblast growth factor 23 levels. db/db mice on the phosphorus-rich diet also presented with significantly lower body weight, lower homeostasis model assessment of insulin resistance index, and hypertrophic cardiomyopathy. Thus, we provide a murine model of phosphate nephropathy and secondary hyperparathyroidism, which can be used for future pharmacologic and pathophysiologic studies to analyze the effect of hyperphosphatemia on renal, metabolic, and cardiovascular phenotypes.

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“…23 In another mouse model of glomerulonephritis, P-Selectin-deficient mice show increased proteinuria, glomerular damage and mortality. 24 However, although these animal models have the potential to provide a link between decreased production of P-Selectin and increased risk of renal disease, there may be a complication in the interpretation the results. This complication was first identified by Bygrave et al, who discovered that the 129-derived chromosome 1 segment used for gene-targeted deletions may itself produce symptoms of autoimmunity.…”

Section: Meta-analysismentioning

confidence: 99%

Variation in the upstream region of P-Selectin (SELP) is a risk factor for SLE

et al. 2009

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Systemic lupus erythematosus (SLE) is a complex autoimmune disease. Genome-wide linkage studies implicated a region containing the adhesion molecule P-Selectin. This family-based study revealed two regions of association within P-Selectin . The strongest signal, from a 21.4-kb risk haplotype, stretched from the promoter into the first two consensus repeat (CR) regions ( P =8 × 10 −4 ), with a second association from a 14.6-kb protective haplotype covering CR 2–9 ( P =0.0198). The risk haplotype is tagged by the rare C allele of rs3753306, which disrupts the binding site of the trans-activating transcription factor HNF-1 . One other variant (rs3917687) on the risk haplotype was significant after permutation ( P 10000 <1 × 10 −5 ), replicated in independent pseudo case-control analysis and was significant by meta-analysis ( P = 4.37 × 10 −6 ). A third associated variant on the risk haplotype (rs3917657) replicated in 306 US SLE families and was significant in a joint UK-SLE data set after permutation. The protective haplotype is tagged by rs6133 (a non-synonymous variant in CR8 ( P =9.00 × 10 −4 ), which also shows association in the pseudo case-control analysis ( P =1.09 × 10 −3 ) and may contribute to another signal in P-Selectin . We propose that polymorphism in the upstream region may reduce expression of P-Selectin, the mechanism by which this promotes autoimmunity is unknown, although it may reduce the production of regulatory T cells.

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P-selectin deficiency exacerbates experimental glomerulonephritis: a protective role for endothelial P-selectin in inflammation

Cited by 117 publications

References 47 publications

Excreted urinary mediators in an animal model of experimental immune nephritis with potential pathogenic significance

Excreted urinary mediators in an animal model of experimental immune nephritis with potential pathogenic significance

A Murine Model of Phosphate Nephropathy

Variation in the upstream region of P-Selectin (SELP) is a risk factor for SLE

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