In situ expression and soluble form of P-selectin in human glomerulonephritis

Abstract

To clarify the early involvement of cellular adhesion molecules in human glomerulonephritis, we investigated P-selectin and high endothelial venules' (HEVs) marker MECA-79 expression in kidney specimens by immunohistochemical and in situ hybridization analyses, and measured serum and urinary soluble P-selectin levels by enzyme-linked immunosorbent assay. In normal controls, P-selectin and MECA-79 expression were negative in glomeruli (N = 4), and serum soluble P-selectin levels were 114.3 +/- 36.8 ng/ml (mean +/- SEM, N = 12). Soluble P-selectin was not detectable in urine of all cases. In proliferative glomerulonephritis involving rapidly progressive glomerulonephritis (N = 6), IgA nephropathy (N = 26), lupus nephritis (N = 7) and acute glomerulonephritis (N = 2), both glomerular and interstitial P-selectin expression were up-regulated. Glomerular P-selectin expression correlated positively with local cellular accumulation, endocapillary proliferation and CD41b (platelet) staining. Interstitial P-selectin expression showed a positive correlation with the grade of local cellular infiltrates. P-selectin mRNA signals detected by in situ hybridization were only observed on capillary or venous endothelium in the interstitium, but not in glomeruli. In addition, MECA-79 was expressed on the plump endothelial cells at the cortico-medullary junction (outer medulla). Serum soluble P-selectin levels were significantly higher in patients with proliferative glomerulonephritis, especially in glomerular and interstitial P-selectin positive staining, and correlated with glomerular endocapillary proliferation. These observations suggested that P-selectin was associated with both glomerular and interstitial leukocyte accumulation in human glomerulonephritis, and might be expressed by two distinct mechanisms that are the activated platelets in glomeruli and the de novo expression in the interstitial lesions that correlated with MECA-79 expression as HEVs like vessels, and serum soluble P-selectin may be a useful marker for predicting in situ P-selectin expression associated with glomerular endocapillary proliferation in nephritis.

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

“…Therefore, serum levels of these 4 molecules were next assayed at serial time points following the glomerular insult. In all 4 strains of mice, serum levels of VCAM-1, P-selectin, and CXCL16 reached a peak on day 7 (not day 14), to a fairly similar degree in all 4 strains. Representative ELISA results are shown in Figure 3.…”

“…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). However, it has not been specifically measured in the urine of mice or in the urine of patients with lupus or immune nephritis.…”

“…Finally, we sought to determine the pathophysiologic relevance of these 4 molecules in immune nephritis. Some information is already available concerning the role of VCAM-1, P-selectin, and TNFRI in renal disease (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19), as discussed below. However, much less is known about the role of CXCL16, which is a chemokine expressed on dendritic cells and macrophages.…”

Fractalkine and its receptor, CX3CR1, promote hypertensive interstitial fibrosis in the kidney

“…Macrophage infiltration was observed predominantly in the outer medulla, which is similar to those in other models, such as ischemiareperfusion, 6 kidney fibrosis 5 and human kidney disease. 15 This result is partly because high endothelial venules (HEVs) that express MECA-79 affect infiltrating cells into kidneys and could be detected in outer medulla; 16 however, we did not examine whether HEVs-like vessels in the outer medulla expressed fractalkine/CX3CL1 in this particular model. Recently, fractalkine/CX3CL1 and CX3CR1 have been reported to contribute to fibrogenesis.…”

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

“…No P-Selectin mRNA transcript was detected in the glomerulus of renal cases, despite an increased expression of glomerular P-Selectin. 26 The increase in protein expression may reflect the release of stored P-Selectin from storage granules rather than increased gene expression, as P-Selectin is constitutively produced in the secretory granules of platelets (a-granules) and endothelial cells (Weibel-Palade bodies), but is not expressed on the cell surface until an appropriate stimulus is provided. 14 Given the evidence presented above, it is intriguing to hypothesize that variants in P-Selectin may have a role in renal lupus, but we do not have sufficient power within the UK SLE cohort used for this paper to assess whether the association in P-Selectin is stronger for UK SLE families in which the affected offspring has renal disease.…”