These studies establish an important fibrogenic role for PAI-1 in the renal fibrogenic response. The results demonstrate that one important fibrosis-promoting function of PAI-1 is its role in the recruitment of fibrosis-inducing cells, including myofibroblasts and macrophages.
We measured the serum levels of soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble E-selectin (sE-selectin) and soluble intercellular adhesion molecule-1 (sICAM-1) in 72 patients with systemic lupus erythematosus (SLE) (including patients with active nephritis) and 33 normal control subjects, to investigate the correlation between levels of adhesion molecules and disease and histological activity. Serum samples were obtained at the time of renal biopsy in 27 patients with lupus nephritis. The 27 patients were divided into groups according to the World Health Organization (WHO) class as follows: class I + II, n = 11; class III + IV, n = 13 and class V, n = 3. We also determined the activity index (AI) in these 27 renal biopsy specimens. We obtained serial measurements of the serum levels of soluble adhesion molecules in 11 patients to examine the difference between active and remission stages. The serum level of sVCAM-1, but not sE-selectin or sICAM-1, was correlated with parameters of SLE disease activity, including the SLE disease activity index score, the anti-double stranded DNA antibody titer, the C3 level, the C4 level and the CH50 level. The serum levels of sVCAM-1, sE-selectin and sICAM-1 were significantly higher in patients with SLE than in controls (P = 0.006, P = 0.0005 and P = 0.04, respectively). The serum level of sVCAM-1 was significantly higher in patients with active lupus nephritis (WHO classes III and IV) than in patients in inactive lupus nephritis (WHO classes I and II) (P = 0.0016). The sVCAM-1 level was significantly elevated in patients with an AI > or = 4 compared with patients with an AI < 4 (P = 0.0025). The sVCAM-1 level decreased significantly during remission (P = 0.0033). The serum level of sVCAM-1 was elevated in patients with active lupus nephritis (WHO classes III and IV) and in patients with high AI scores. The serum level of sVCAM-1 was correlated with the SLE disease activity and decreased during remission. Therefore, the sVCAM-1 level may be a useful marker of lupus nephritis activity.
We characterized the proliferative action of prostaglandins (PGs) in relation to their membrane receptors on rat hepatocytes in primary culture. PGs in the order 16,16-dimethyl PGE2 > PGE2 > PGF2alpha >> PGD2 augmented epidermal growth factor (EGF)/insulin-induced DNA synthesis, assessed by [(3)H]thymidine incorporation, in a concentration-dependent manner, whereas PGs alone did not stimulate basal DNA synthesis without EGF and insulin. The cells exhibited [(3)H]PGE2 binding sites that were displaced by unlabeled PGs in the order PGE1 = PGE2 > PGF2alpha > PGD2. PGE2 inhibited glucagon-stimulated adenosine 3',5'-cyclic monophosphate (cAMP) accumulation concentration dependently. The mean effective concentration for DNA synthesis, median inhibitory concentration for cAMP accumulation, and dissociation constant for [(3)H]PGE2 binding at 25 degrees C were almost identical (approximately 70 nM). Treatment of the cells with pertussis toxin (100 ng/ml), which ADP-ribosylated most of the 41-kDa substrate, abolished the proliferative effects of PGs. We detected the expression of mRNA of the EP3 subtype PGE2 receptor using reverse transcription-polymerase chain reaction. Moreover, an EP3 agonist, enprostil, but not the EP1 agonist 17-phenyl-trinor-PGE2 or the EP2/EP4 agonist 11-deoxy-PGE1, stimulated EGF/insulin-induced DNA synthesis. These results indicate that PGs act as comitogenic growth factors through the EP3 subtype PGE2 receptor coupled with G(i) protein in cultured rat hepatocytes.
Objective Continuous positive airway pressure (CPAP) is an effective treatment for obstructive sleep apnea (OSA). After performing an initial titration study, most physicians do not have the CPAP equipment retitrated unless the patient complains about the CPAP use. Several automated CPAP devices are used clinically that can detect upper airway obstructive events and provide information about residual events while patients are on CPAP. The aim of this study was to compare the apnea-hypopnea index (AHI) determined by automated CPAP devices to that obtained from polysomnography. Methods Patients with OSA underwent polysomnography for CPAP titration using the REMstar Auto Mseries. The initial two hours of CPAP titration were spent at a subtherapeutic pressure of 4 cmH2O so that more breathing events could be observed. The correlations between the simultaneous determination of the AHI with polysomnography (AHI-PSG) and the automated device (AHI-RAM) during the subtherapeutic, therapeutic and overall phases were evaluated. In addition, the apnea index (AI) and the hypopnea index (HI) were each evaluated separately. Results Sixty patients were enrolled. The mean AHI on diagnostic PSG was 35.2±2.6 events/hour. Strong correlations were observed between the AHI-PSG and the p<0.001; therapeutic: r=0.824, p<0.001; overall: r=0.927, p<0.001). A slightly stronger correlation was observed between the AI values, whereas a weaker correlation was observed between the HI values in all three phases. Conclusion Strong correlations between the AHI-PSG and the AHI-RAM were observed. The correlations were weakened when the analysis was limited to the HI and the therapeutic phase.
Background: Bone morphogenetic protein-7 (BMP-7) plays a critical role in renal development, accelerates recovery from acute renal injury, and more recently it has been shown to delay progressive renal disease. The present study was designed to investigate the effect of BMP-7 on interstitial fibrosis in the rat protein-overloaded model. Methods: Renal disease was induced in 26 rats by daily intraperitoneal injections of bovine serum albumin (BSA); controls (n = 28) were injected with saline. Half of the rats in each group were treated with human recombinant BMP-7 (300 µg/kg i.p. 3 times weekly) and half with placebo. Animals were killed after 3 or 6 weeks. Results: Compared to the saline control groups, the BSA groups had evidence of chronic renal disease: significantly increased urinary protein excretion rates; total kidney collagen content, and increased fibronectin and collagen III interstitial areas. By 6 weeks the BSA + BMP-7 group compared to the BSA + placebo group had a nonsignificant decrease in blood urea nitrogen (40 ± 13 vs. 46 ± 11 mg/dl), total kidney collagen (10.8 ± 2.1 vs. 12.2 ± 3.5 µg/kidney), fibronectin interstitial area (23 ± 4 vs. 25 ± 8%) and collagen III interstitial area (22 ± 6 vs. 28 ± 7%). Despite these results, renal gene expression profiles actually predicted worse fibrosis in the BSA + BMP-7 group with significantly higher total kidney mRNA levels for α1(III) procollagen (2.8 ± 0.5 vs. 1.6 ± 0.6, p < 0.05) and fibronectin at 6 weeks (1.9 ± 0.3 vs. 1.2 ± 0.5, p < 0.05). Renal BMP-7 mRNA levels at 6 weeks were significantly increased in the BSA + placebo group compared to the saline + placebo group with no difference between the BSA + BMP-7 and the BSA + placebo groups. Both cortical and medullary tubules expressed BMP-7 protein but BMP-7 was only detected in the tubular lumina and urine of proteinuric animals. Conclusions: In rats with protein-overload proteinuria, renal tubules continue to express BMP-7 but some of the endogenous protein is secreted into the urinary space. Administration of exogenous recombinant BMP-7 had no effect on proteinuria but was associated with a nonsignificant trend towards less interstitial fibrosis at 6 weeks despite significantly higher kidney extracellular matrix gene mRNA levels. These findings suggest that BMP-7 treatment may have anti-fibrotic effects through enhancement of matrix turnover, although overall these effects are modest in proteinuric states in the absence of significant tubular epithelial cell apoptosis and epithelial-mesenchymal transition.
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