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The severity of glomerular endothelial cell injury is associated with infiltrating macrophage heterogeneity in endocapillary proliferative glomerulonephritis.

ABSTRACT: Endocapillary proliferation occurs in various types of glomerulonephritis (GN), with varying prognoses. We examined 42 renal biopsy samples representing endocapillary proliferative lesions from post-streptococcal acute GN (PSAGN), Henoch-Schönlein purpura nephritis (HSPN), and lupus nephritis (LN). In PSAGN, the glomerular capillary network was maintained, although severe lesions displayed dots or short, curved lines, indicating CD34-positive capillaries and suggesting capillary obstruction. Conversely, patients with LN and HSPN displayed obstruction of CD34-positive capillaries with dissociation from the glomerular basement membrane even in mild lesions. According to computer-assisted morphologic analysis, the cell density did not differ between the diseases. However, in PSAGN, the number of capillary loops was significantly increased, with a larger glomerular capillary luminal area than in the other groups. In addition, the number and frequency of CD163-positive cells (M2 macrophages) tended to be higher in PSAGN, while there were no significant differences in the number of CD68-positive (total) macrophages. These results indicate that in PSAGN, endothelial cell damage is less severe, and angiogenesis may be promoted. The severity of endothelial cell injury in each disease may be associated with differences in infiltrating inflammatory cell phenotypes.

SUBMITTER: Arai M

PROVIDER: S-EPMC8233400 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:Glomerular endothelium dysfunction, which plays a crucial role in the pathogenesis of early diabetic nephropathy, might be caused by circulating metabolic abnormalities. Platelet microparticles, extracellular vesicles released from activated platelets, have recently emerged as a novel regulator of vascular dysfunction. METHODS:We studied the effects of platelet microparticles on glomerular endothelial injury in early diabetic nephropathy in rats with streptozotocin-induced diabetes and primary rat glomerular endothelial cells. Isolated platelet microparticles were measured by flow cytometry. RESULTS:Plasma platelet microparticles were significantly increased in diabetic rats, an effect inhibited in aspirin-treated animals. In cultured glomerular endothelial cells, platelet microparticles induced production of reactive oxygen species, decreased nitric oxide levels, inhibited activities of endothelial nitric oxide synthase and SOD, increased permeability of the glomerular endothelium barrier, and reduced thickness of the endothelial surface layer. Conversely, inhibition of platelet microparticles in vivo by aspirin improved glomerular endothelial injury. Further analysis showed that platelet microparticles activated the mammalian target of rapamycin complex 1 (mTORC1) pathway in glomerular endothelial cells; inhibition of the mTORC1 pathway by rapamycin or raptor siRNA significantly protected against microparticle-induced glomerular endothelial injury in vivo and in vitro. Moreover, platelet microparticle-derived chemokine ligand 7 (CXCL7) contributed to glomerular endothelial injury, and antagonizing CXCL7 using CXCL7-neutralizing antibody or blocking CXCL7 receptors with a competitive inhibitor of CXCR1 and CXCR2 dramatically attenuated such injury. CONCLUSIONS:These findings demonstrate a pathogenic role of platelet microparticles in glomerular endothelium dysfunction, and suggest a potential therapeutic target, CXCL7, for treatment of early diabetic nephropathy.

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The severity of glomerular endothelial cell injury is associated with infiltrating macrophage heterogeneity in endocapillary proliferative glomerulonephritis.

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