Connective tissue growth factor-(CTGF, CCN2)--a marker, mediator and therapeutic target for renal fibrosis.

Connective tissue growth factor (CTGF, CCN2) is a key mediator of tissue fibrosis. CCN2 plays an important role in the development of glomerular and tubulointerstitial fibrosis in progressive kidney diseases. In this review, we discuss the biology of CCN2 with a focus on the regulation of CCN2 gene, cellular mechanisms of profibrotic CCN2 effects and the current in vivo and in vitro evidence for the role of CCN2 in the development of renal fibrosis. We also discuss the therapeutic potential of targeting CCN2 for the treatment of renal fibrosis.

Lipopolysaccharide modifies amiloride-sensitive Na+ transport processes across human airway cells: role of mitogen-activated protein kinases ERK 1/2 and 5.

Bacterial lipopolysaccharides (LPS) are potent inducers of proinflammatory signaling pathways via the activation of nuclear factor-kappa B (NF-kappaB) and mitogen-activated protein kinase (MAPK), causing changes in the processes that control lung fluid homeostasis and contributing to the pathogenesis of lung disease. In human H441 airway epithelial cells, incubation of cells with 15 microg ml(-1) LPS caused a significant reduction in amiloride-sensitive I (sc) from 15 +/- 2 to 8 +/- 2 microA cm(-2) (p = 0.01, n = 13) and a shift in IC(50) amiloride of currents from 6.8 x 10(-7) to 6.4 x 10(-6) M. This effect was associated with a decrease in the activity of 5 pS, highly Na(+) selective, amiloride-sensitive <1 microM channels (HSC) and an increase in the activity of approximately 18 pS, nonselective, amiloride-sensitive >10 microM cation channels (NSC) in the apical membrane. LPS decreased alphaENaC mRNA and protein abundance, inferring that LPS inhibited alphaENaC gene expression. This correlated with the decrease in HSC activity, indicating that these channels, but not NSCs, were comprised of at least alphaENaC protein. LPS increased NF-kappaB DNA binding activity and phosphorylation of extracellular signal-related kinase (ERK)1/2, but decreased phosphorylation of ERK5 in H441 cells. Pretreatment of monolayers with PD98059 (20 microM) inhibited ERK1/2 phosphorylation, promoted phosphorylation of ERK5, increased alphaENaC protein abundance, and reversed the effect of LPS on I (sc) and the shift in amiloride sensitivity. Inhibitors of NF-kappaB activation were without effect. Taken together, our data indicate that LPS acts via ERK signaling pathways to decrease alphaENaC transcription, reducing HSC/ENaC channel abundance, activity, and transepithelial Na(+) transport in H441 airway epithelial cells.

Development of an outpatient finger-prick glomerular filtration rate procedure suitable for epidemiological studies.

Development of an outpatient finger-prick glomerular filtration rate (GFR) procedure suitable for epidemiological studies. In clinical practice, reference GFR procedures are rarely used; in large-scale research studies, a great deal of effort and experience is required to obtain them, which is a considerable disincentive to using GFR as an end point. The major problem for both clinical staff and the subject is the length of time that the procedure takes, requiring continuous attendance in the outpatient clinic or its vicinity. Using iohexol as a marker, we therefore propose an alternative approach, which addresses this fundamental deterrent to a more widespread use of GFR measurement. Eighty-two GFR measurements were performed in a mixture of healthy subjects and patients with differing degrees of renal impairment with a wide range of GFRs. Serum was obtained from blood samples to enable a reference GFR to be calculated. Blood spots were collected on filter paper at the same intervals (120, 180, and 240 min), allowed to dry, and then sent through the post. Serum and blood spots were analyzed simultaneously for each individual by automated reverse-phase high-pressure liquid chromatography. Standard linear regression analyses confirmed a good agreement (r2 = 0.953) between the iohexol serum GFR and iohexol blood spots GFR. Bland-Altman analysis confirmed that there was no concentration bias. Paired comparisons (Wilcoxon's paired signed rank test) showed no significant difference between the two measurements. Capillary sampling is simple, effective, and significantly reduces the time and costs of performing plasma clearance GFR measurements. This approach will make the GFR measurement more accessible for clinical practice and large-scale epidemiological studies may become feasible.