Tubulointerstitial fibrosis is recognized as a key determinant of progressive chronic kidney disease (CKD). Fucoidan, a sulphated polysaccharide extracted from brown seaweed, exerts beneficial effects in some nephropathy models. The present study evaluated the inhibitory effect of oligo-fucoidan (800 Da) on renal tubulointerstitial fibrosis. We established a mouse CKD model by right nephrectomy with transient ischemic injury to the left kidney. Six weeks after the surgery, we fed the CKD mice oligo-fucoidan at 10, 20, and 100 mg/kg/d for 6 weeks and found that the oligo-fucoidan doses less than 100 mg/kg/d improved renal function and reduced renal tubulointerstitial fibrosis in CKD mice. Oligo-fucoidan also inhibited pressure-induced fibrotic responses and the expression of CD44, β-catenin, and TGF-β in rat renal tubular cells (NRK-52E). CD44 knockdown downregulated the expression of β-catenin and TGF-β in pressure-treated cells. Additional ligands for CD44 reduced the anti-fibrotic effect of oligo-fucoidan in NRK-52E cells. These data suggest that oligo-fucoidan at the particular dose prevents renal tubulointerstitial fibrosis in a CKD model. The anti-fibrotic effect of oligo-fucoidan may result from interfering with the interaction between CD44 and its extracellular ligands.

BackgroundHeart failure is a highly prevalent cardiovascular complication among patients receiving long‐term hemodialysis, but the benefits of carvedilol, bisoprolol, and metoprolol controlled release/extended release on the outcomes of these patients remain unclear. In this study, we address the use of these 3 β‐blockers and their associations with mortality.Methods and ResultsLong‐term hemodialysis patients, aged ≥35 years, with new‐onset heart failure and receiving various medications were identified through the use of 1999–2010 data from the Taiwan National Health Insurance Research Database. From the total of 4435 heart failure patients, we selected 1700 new users of the 3 β‐blockers (study group) and 1700 nonusers (control group), by using matched cohorts according to their propensity scores, and then compared the 5‐year all‐cause mortality rates by using Cox proportional hazard regressions and time‐dependent covariate adjustment. During 3944 person‐years of follow‐up, 666 (39.2%) deaths occurred within the study group, compared with 918 (54%) deaths during 2893 person‐years of follow‐up in the control group. The 5‐year mortality rate for the study (control) group was 54.5% (70.3%); P<0.001. Adjusted hazard regression analyses revealed that the therapeutic effects of β‐blockers remained significant for all‐cause mortality (hazard ratio 0.80, 95% CI 0.72 to 0.90). Subgroup analyses revealed that patients in the study group receiving β‐blockers plus renin‐angiotensin system antagonists exhibited the lowest mortality rate, while the highest mortality rate was found among patients in the control group receiving neither β‐blockers nor renin‐angiotensin system antagonists.ConclusionsThis study demonstrates that the 3 β‐blockers were associated with improved survival in long‐term hemodialysis patients with heart failure.

Epidermal growth factor (EGF) and endothelin-1 (ET-1) have been shown to be involved in proliferation and autoregeneration of renal tubular cells. This study aims to investigate the regulatory mechanism of ET-1-mediated EGF receptor (EGFR) transactivation in rat renal tubular cells (NRK-52E). Exposure of NRK-52E cells to ET-1 was found to stimulate the phosphorylation of EGFR and induce reactive oxygen species (ROS) generation. Both NAD(P)H oxidase inhibitor, diphenyliodonium (DPI) and ROS scavenger N-acetylcysteine (NAC), inhibited EGFR transactivation and extracellular signal-regulated kinase (ERK) phosphorylation caused by ET-1. In contrast, blockade of EGFR by AG1478 inhibited the phosphorylation of ERK but not ROS generation following ET-1 exposure. We found that the catalytic cysteine of Src homology 2-containing phosphotyrosine phosphatase (SHP-2) was transiently oxidized by ET-1 treatment in a modified malachite green phosphatase assay. In EGFR co-immunoprecipitation, SHP-2 was also found to interact with EGFR following ET-1 treatment. In SHP-2 knockdown NRK-52E cells, ET-1-induced EGFR transactivation was dramatically elevated and not influenced by NAC. However, GM6001 (an MMP inhibitor) and heparin binding (HB)-EGF neutralizing antibody suppressed this elevation. Our data suggest that ROS-mediated oxidation of SHP-2 is essential for HB-EGF-mediated EGFR transactivation in ET-1 signaling pathway in NRK-52E cells.