The authors found a significantly higher prevalence of daytime somnolence in 201 patients with PD compared with 214 age- and sex-matched healthy control subjects (Epworth Sleepiness Scale score 5.6 vs 4.6). The prevalence of "sleep attacks" (SA) was about seven times higher in patients with PD than in control subjects (13.9% vs 1.9%; p < 0.0005). Multivariate analysis demonstrated that a higher dose of levodopa and longer duration of disease significantly predicted for SA in patients with PD. Epworth Sleepiness Scale scores of > or =10 had 71.4% sensitivity and 88.4% specificity for SA.

Emerging evidence suggests that mesangial cell-derived monocyte chemoattractant protein-1 (MCP-1) is a potentially important mediator of glomerular monocyte infiltration. Interleukin-1 beta (IL-1) has been found in glomeruli during inflammation, and is a potent inducer of MCP-1 expression by mesangial cells. Analysis of the promoter region of the human MCP-1 gene demonstrates several putative binding sites for transcription activating factors, including recognition elements for the IL-1-inducible transcription factor, nuclear factor-kappa B (NF-kappa B). This study investigated the role of NF-kappa B in IL-1-induced MCP-1 expression by human mesangial cells. We found that treating mesangial cells with IL-1 resulted in the rapid activation (within 30 min) and nuclear translocation of NF-kappa B. NF-kappa B activation could be blocked by preventing the proteolytic degradation of I kappa B, the cytoplasmic inhibitor of NF-kappa B, with the protease inhibitor tosyl-phe-chloromethylketone (TPCK). Inhibition of NF-kappa B with TPCK correlated with a dose-dependent reduction in IL-1-induced MCP-1 mRNA levels. Conversely, raising intracellular cyclic-AMP levels, or exposing mesangial cells to herbimycin A, treatments that block IL-1-induced MCP-1 mRNA expression, significantly attenuated NF-kappa B activation. Finally, blocking the synthesis of one of the protein subunits of NF-kappa B with an antisense oligonucleotide decreased MCP-1 mRNA levels in response to IL-1. These data suggest that MCP-1 gene transcription may be mediated, in part, by the transcription factor NF-kappa B.

No abstract

Hyperlipidemia has been associated with glomerulosclerosis and a glomerular monocyte infiltrate in models of progressive renal insufficiency. The pathogenesis of hyperlipidemia-induced renal injury remains unknown. We postulated that the effect of hyperlipidemia may be mediated through LDL-induced activation of mesangial cells, which have recently been shown to possess LDL receptors. To test this hypothesis, cultured human mesangial cells were co-incubated with human LDL. Monolayers treated with LDL demonstrated a greater level of tissue culture supernatant fibronectin than control mesangial cells. This correlated with enhanced expression of fibronectin mRNA in LDL-treated mesangial cells. Additionally, LDL conditioning of mesangial cells caused a dose- and time-dependent increase in the expression of monocyte chemoattractant protein-1 mRNA, a monocyte specific chemotactic factor, as well as an increase in the monocyte chemotactic activity of mesangial supernatants. Thus, the deleterious effects of hyperlipidemia on the kidney may be mediated by the mesangial cell through an increase in production of mesangial matrix and recruitment of inflammatory cells to the glomerulus.

Interleukin-1beta (IL-1beta) significantly influences renal cellular function through the induction of several gene products. The molecular mechanisms involved in gene regulation by IL-1beta are poorly understood; however, the appearance of novel tyrosine phosphoproteins in IL-1beta-treated cells suggests that IL-1beta may function through tyrosine phosphoprotein intermediates. The mitogen-activated protein (MAP) kinases are tyrosine phosphoproteins that could potentially mediate the effects of IL-1beta. Protein tyrosine phosphorylation following IL-1beta treatment may be dependent on redox changes since the IL-1beta receptor is not a protein-tyrosine kinase and oxidation has been shown to induce tyrosine phosphorylation. In this report we demonstrate that conditioning human glomerular mesangial cells with IL-1beta results in the tyrosine phosphorylation and activation of two members of the MAP kinase family, extracellular signal-regulated protein kinase 2 (ERK2) and p54 Jun-NH2-terminal kinase (JNK). This effect of IL-1beta is abrogated by pretreating cells with the antioxidants N-acetyl-L-cysteine or dithiothreitol. Furthermore, the effects of IL-1beta on ERK and JNK activation are reproduced by treating mesangial cells with membrane-permeable oxidants. IL-1beta and oxidants also cause phosphorylation and activation of the upstream ERK regulatory element MAP kinase kinase. Interestingly, IL-1beta, but not exogenous oxidants, causes phosphorylation of the upstream JNK activator, JNK kinase. These data indicate that IL-1beta activates ERK2 through an oxidation-dependent pathway. Exogenous oxidants and IL-1beta activate JNK through different upstream mechanisms; however, antioxidant inhibition of JNK activation indicates that endogenous oxidants may play a role in IL-1beta-induced JNK activation. Thus IL-1beta may affect mesangial cell function by activating MAP kinases, which can then regulate gene transcription. Furthermore, reactive oxygen species released during inflammatory glomerular injury may also affect mesangial function through a MAP kinase signal.