Advanced glycation end-products induce heparanase expression in endothelial cells by the receptor for advanced glycation end products and through activation of the FOXO4 transcription factor.

As an endo-ß (1-4)-D: -glucuronidase, heparanase can specifically cleave carbohydrate chains of heparan sulfate (HS) and has been implicated in development of endothelial cells dsyfunction. The advanced glycation end products (AGEs) play a pivotal role in the pathology of diabetic complications. In the present study, we investigated the effect of AGE-bovine serum albumin (AGE-BSA) on heparanase expression in human microvascular endothelial cells (HMVECs) and the underlying molecular mechanisms. The results indicated that in vitro direct exposure of HMVECs to AGE-BSA (300, 1000, and 3000 µg/ml) could increase heparanase mRNA and protein expression in a dose and time-dependent manner. The effect of 1000 µg/ml AGE-BSA could be abolished by neutralization with antibody of the receptor for advanced glycation end products (RAGE). Moreover, pretreatment with inhibitors of nuclear factor-κB (NF-κB) or PI3-kinase did not affect heparanase expression induced by AGE-BSA. Nevertheless, small interference RNA (siRNA) for transcriptional factor FOXO4 could reduce the increase of heparanase expression in HMVECs induced by 1000 µg/ml AGE-BSA. These results suggest that AGEs could induce heparanase expression in HMVECs by RAGE and predominantly through activation of the FOXO4 transcription factor.

Central administration of kisspeptin-10 inhibits water and sodium excretion of anesthetized male rats and the involvement of arginine vasopressin.

AIM: To investigate the effect of hypothalamus kisspeptin on water and sodium excretion and the possible mechanism. METHOD: The intracerebroventricular (icv) administration and radioimmunoassay were used to observe the effect of kisspeptin-10 on urine flow, sodium and potassium excretion, plasma arginine vasopressin (AVP), and atrial natriuretic peptide (ANP) concentrations in anesthetized male rats. The mediation of renal sympathetic nerve was also investigated by studies conducted on rats with bilateral renal sympathetic denervation. RESULTS: The urine flow, sodium excretion, and free water clearance decreased significantly by icv injection of 5 nmol kisspeptin-10 (p < 0.05) from 30 to 60 min post-injection. Meanwhile, plasma AVP concentrations increased significantly 30 min after the icv injection of 5 nmol kisspeptin-10 (p < 0.05), whereas the equal dose of kisspeptin-10 did not significantly change plasma ANP concentrations. The mean arterial blood pressure, heart rate, and potassium excretion did not significantly change during the experiment. Furthermore, pretreatment with 5 nmol kisspeptin-10 could still significantly decrease urine flow and sodium excretion in renal sympathetic denervated rats. CONCLUSION: Central administration of kisspeptin-10 could inhibit sodium excretion and urine flow in anesthetized male rats, which is probably mediated by increasing the plasma AVP concentration and is independent of plasma ANP concentration and renal sympathetic nerve activity.

Orphanin FQ and glutamate connection in the regulation of gonadotropin-releasing hormone secretion in the preoptic area of conscious male rats.

Utilizing the method of push-pull perfusion and radioimmunoassay (RIA), the secretory profile of gonadotropin-releasing hormone (GnRH) in the preoptic area (POA) and serum-luteinizing hormone (LH) levels were examined in conscious male rats after administration of [Nphe(1)]NC(1-13)NH(2), a competitive antagonists of the opioid receptor-like 1 receptor (ORL1 receptor) which is endogenous receptor for Orphanin FQ (OFQ). Glutamate release in the POA was also measured by high-performance liquid chromatography (HPLC) after perfusion of [Nphe(1)]NC(1-13)NH(2), i.e. NC13. The results showed that GnRH secretion from the POA and serum LH levels was increased significantly 40 min and 60 min, respectively after perfusion of 2 and 20 mmol/L NC13 in freely moving male rats (p<0.05). Pretreatment with a glutamate, N-methyl-D-aspartate (NMDA) receptor antagonist (MK-801, s.c., 0.2 mg/kg) abolished the increase of GnRH release in the POA induced by 2 mmol/L NC13. Additionally, 20 mmol/L NC13 significantly enhanced glutamate release in the POA at 40 min post-perfusion in a dose-dependent manner. These findings suggest that hypothalamic OFQ/ORL1 receptor system plays a role in the physiological inhibitory control of GnRH secretion in the POA of male rats, and provide evidence for involvement of an OFQ and glutamate pathway in the control of GnRH secretion.

Plasma sRAGE is not associated with urinary microalbumin excretion in type 2 diabetic nephropathy at the early stage.

AIMS: The interaction of advanced glycation end products (AGEs) and the receptor for advanced glycation end products (RAGE) has played an important role in the pathogenesis of diabetic nephropathy. In the present study, we measured the relationship of plasma soluble isoform of RAGE (sRAGE) and urinary microalbumin excretion in the early stage of type 2 diabetic nephropathy. METHODS: 180 patients with early stage of type 2 diabetic nephropathy were recruited into the study. Plasma sRAGE and the characterized AGE carboxymethyllysine (CML) were measured by enzyme-linked immunosorbent assay. RESULTS: Plasma sRAGE positively correlated with the level of CML (R=0.22, P=0.03) while sRAGE was not significantly correlated with the urinary mAlb/Cr (R=0.15, P=NS). On stepwise linear regression analysis, AGE and GFR were the main independent determinants of plasma sRAGE concentration. CONCLUSION: Plasma sRAGE is not significantly associated with urinary microalbumin excretion in the early stage of diabetic nephropathy while it is correlated positively with circulating AGE and negatively with glomerular filtration rate (GFR).