Atrial natriuretic peptide promotes uterine decidualization and a TRAIL-dependent mechanism in spiral artery remodeling.

Atrial natriuretic peptide (ANP) is an important hormone in cardiovascular biology. It is activated by the protease corin. In pregnancy, ANP and corin promote uterine spiral artery remodeling, but the underlying mechanism remains unknown. Here we report an ANP function in uterine decidualization and TNF-related apoptosis-inducing ligand-dependent (TRAIL-dependent) death in spiral arterial smooth muscle cells (SMCs) and endothelial cells (ECs). In ANP- or corin-deficient mice, uterine decidualization markers and TRAIL expression were decreased, whereas in cultured human endometrial stromal cells (HESCs), ANP increased decidualization and TRAIL expression. In uterine spiral arteries from pregnant wild-type mice, SMC and EC loss occurred sequentially before trophoblast invasion. In culture, TRAIL from decidualized HESCs induced apoptosis in uterine SMCs, but not in ECs with low TRAIL receptor expression. Subsequently, cyclophilin B was identified from apoptotic SMCs that upregulated endothelial TRAIL receptor and caused apoptosis in ECs. These results indicate that ANP promotes decidualization and TRAIL expression in endometrial stromal cells, contributing to sequential events in remodeling of spiral arteries, including SMC death and cyclophilin B release, which in turn induces TRAIL receptor expression and apoptosis in ECs.

Role of corin in trophoblast invasion and uterine spiral artery remodelling in pregnancy.

In pregnancy, trophoblast invasion and uterine spiral artery remodelling are important for lowering maternal vascular resistance and increasing uteroplacental blood flow. Impaired spiral artery remodelling has been implicated in pre-eclampsia, a major complication of pregnancy, for a long time but the underlying mechanisms remain unclear. Corin (also known as atrial natriuretic peptide-converting enzyme) is a cardiac protease that activates atrial natriuretic peptide (ANP), a cardiac hormone that is important in regulating blood pressure. Unexpectedly, corin expression was detected in the pregnant uterus. Here we identify a new function of corin and ANP in promoting trophoblast invasion and spiral artery remodelling. We show that pregnant corin- or ANP-deficient mice developed high blood pressure and proteinuria, characteristics of pre-eclampsia. In these mice, trophoblast invasion and uterine spiral artery remodelling were markedly impaired. Consistent with this, the ANP potently stimulated human trophoblasts in invading Matrigels. In patients with pre-eclampsia, uterine Corin messenger RNA and protein levels were significantly lower than that in normal pregnancies. Moreover, we have identified Corin gene mutations in pre-eclamptic patients, which decreased corin activity in processing pro-ANP. These results indicate that corin and ANP are essential for physiological changes at the maternal-fetal interface, suggesting that defects in corin and ANP function may contribute to pre-eclampsia.

Herb medicine Gan-fu-kang attenuates liver injury in a rat fibrotic model.

AIM OF THE STUDY: To verify therapeutic effects of Gan-fu-kang (GFK), a traditional Chinese medicine compound, in a rat model and to investigate the underlying mechanisms. MATERIALS AND METHODS: Liver fibrosis was established by 12 weeks of carbon tetrachloride (CCl(4)) treatment (0.5mg/kg, twice per week) followed by 8 weeks of "recovery" in rats. Rats randomly received GFK (31.25, 312.5 and 3125 mg/kg/day, p.o.) or vehicle from weeks 9 to 20, and were sacrificed at the end of week 20 for histological, biochemical, and molecular biological examinations. In a separate set of experiments, rats received 12 weeks of CCl(4) treatment, concomitant with GFK (312.5mg/kg/day, p.o.) during the same period in some subjects, but were then sacrificed immediately. An additional group of rats receiving no CCl(4) treatment served as normal controls. RESULTS AND CONCLUSIONS: (1) CCl(4) treatment resulted in severe liver damage and fibrosis. (2) In the main block of the 20-week study, GFK attenuated liver damage and fibrosis. (3) In the 12-week study, GFK produced prevention effect against hepatic injury. (4) GFK suppressed the expression of tissue inhibitor of metalloproteinase-1 (TIMP-1), type I collagen, platelet-derived growth factor-BB (PDGF-BB)/PDGF receptor-beta chains (PDGFRbeta) and mitogen-activated protein kinases (MAPKs)/active protein-1 (AP-1) signal pathways. Taken together, these results indicated that GFK could attenuate liver injuries in both settings. Our findings also suggest that the AP-1 pathway is the likely molecular substrate for the observed GFK effects.

[Transforming growth factor-ß1 and Snail1 mediate tubular epithelial-mesenchymal transition in diabetic rats].

The present study was aimed to explore the expressions of transforming growth factor-ß1 (TGF-ß1) and Snail1 in renal tissues of diabetic rats, and their role in tubular epithelial-mesenchymal transition (TEMT). Induced diabetic rats were randomly divided into 2-, 4-, 8-, 12-, 16-, 20-, 24-week and 16wA, 20wA, 24wA groups. The rats in 16wA, 20wA and 24wA groups were treated with insulin to control blood glucose to the normal level from the 13th week. The age-matched rats were set as controls. Blood glucose, 24-hour urine protein, serum creatinine (Scr), kidney index of rats were measured. PAS staining was used to observe the renal pathological changes. Immunohistochemical staining and (or) Western blot were employed to determine the expressions of TGF-ß1, Snail1, E-cadherin, α-smooth muscle actin (α-SMA) and fibronectin (FN) proteins. The expressions of Snail1 and E-cadherin mRNAs in renal cortex were examined by RT-PCR. Blood glucose, 24-hour urine protein, Scr and kidney index increased remarkably in diabetic rats as compared with those in the control groups (P<0.05, P<0.01) and insulin-treated rats (P<0.01). TGF-ß1 and Snail1 protein expressions could not be detected by immunohistochemical staining in the normal renal tissues, however, the strongly positive staining was observed in diabetic rat renal tubules. A time-dependent loss of TGF-ß1 and Snail1 expressions was detected in the kidney of insulin-treated rats. In diabetic rats tubular α-SMA positive staining was seen at the 16th week. E-cadherin expression was lost in diabetic rats. The expressions of TGF-ß1, Snail1 proteins and Snail1 mRNA were significantly up-regulated in diabetic rats, while down-regulated in insulin-treated rats (P<0.01). The expressions of E-cadherin protein and mRNA in the cortex were contrary to the expressions of TGF-ß1 and Snail1. Therefore, TGF-ß1 and Snail1 are possibly involved in the pathogenesis of TEMT in diabetic nephropathy rats.