Although synthesis of VEGF mRNA and protein is not increased during ischemia reperfusion injury, pre-existing VEGF in the tubular cell cytoplasm redistributes to the basolateral aspect of the cells. These data suggest that the kidney may have evolved unique patterns of VEGF regulation to cope with acute hypoxia.
Activation of nuclear factor‐kappa B (NF‐κB) is one of the most important pro‐inflammatory mechanisms in disease. In this study, we show that 5‐aminoimidazole‐4‐carboxamide ribonucleoside (AICAR), an intermediate in nucleoside metabolism, inhibits signalling by NF‐κB in three cell types, including bovine aortic endothelial cells (BAEC). The block in the NF‐κB signalling pathway occurred beyond degradation of IκB‐α and movement of p65 into the nucleus of BAEC. There was, however, reduced binding of NF‐κB from AICAR‐treated cells to a κB‐consensus oligonucleotide, suggesting that part of the mechanism was a reduction in NF‐κB DNA‐binding activity. Although AICAR is metabolized to ZMP and then adenosine, adenosine had no effect on activation of an NF‐κB reporter. ZMP, however, activates the metabolic stress‐sensing AMP‐activated protein kinase (AMPK). Transfection of active AMPK into BAEC reduced NF‐κB reporter activity compared with a kinase‐dead mutant, suggesting that part of the ability of AICAR to inhibit NF‐κB signalling is due to activation of AMPK. Inhibition of NF‐κB signalling may be important in the anti‐inflammatory action of drugs such as sulfasalazine and methotrexate, which led to the accumulation of AICAR within target cells.
SUMMARYConflicting reports exist regarding the effects of interleukin-10 (IL-10) on mesangial cells. There have been reports of both proliferative and antiproliferative effects, and both proinflammatory and antiinflammatory effects of IL-10 on mesangial cells. However, the potential for IL-10 to affect glomerulonephritis characterized by mesangial proliferation is not known. To test the hypothesis that IL-10 would limit experimental mesangial proliferative glomerulonephritis, IL-10 was administered to rats in which mesangial proliferative glomerulonephritis was induced by administration of anti-Thy 1 antibody. Compared to control treated rats, IL-10 treated rats showed less proliferation, with fewer cells in glomeruli. Glomerular cellular proliferation was reduced, assessed by the numbers of cells within glomeruli expressing either proliferating cell nuclear antigen (PCNA) or bromodeoxyuridine. Glomerular macrophage influx (but not the proportion of glomerular macrophages that were PCNA positive) was reduced by IL-10 administration. There was no significant reduction in glomerular asmooth muscle actin staining. IL-10 treatment resulted in reduced renal IL-1b mRNA expression and reduced glomerular ICAM-1 expression, but renal expression of MCP-1 and osteopontin mRNA was unaltered. This study demonstrates that in experimental mesangial proliferative glomerulonephritis IL-10 diminishes inflammatory cell recruitment and mesangial cell proliferation. The effects of IL-10 in inhibiting mesangial cell proliferation are likely to be due to a combination of direct effects of IL-10 on mesangial cells and effects mediated by macrophages.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.