Arterial wall hypertrophy is ameliorated by α2-adrenergic receptor antagonist or aliskiren in kidneys of angiotensinogen-knockout mice.

BACKGROUND: Arterial hypertrophy and interstitial fibrosis are important characteristics in kidneys of angiotensinogen-knockout (Atg -/-) mice. In these mice, which exhibit polyuria and hypotension, sympathetic nerve signaling is estimated to be compensatorily hyperactive. Furthermore, transforming growth factor (TGF)-ß1 is overexpressed in mice kidneys. To determine whether sympathetic nerve signaling and TGF-ß1 exacerbate arterial hypertrophy and interstitial fibrosis, intervention studies of such signaling are required. METHODS: We performed renal denervation and administered the α2-adrenergic receptor (AR) antagonist, atipamezole, to Atg -/- mice. A renin inhibitor, aliskiren, which was preliminarily confirmed to reduce TGF-ß1 gene expression in kidneys of the mice, was additionally administered to assess the effect on the arterial hypertrophy and interstitial fibrosis. RESULTS: Norepinephrine content in kidneys of Atg -/- mice was three times higher than in kidneys of wild-type mice. Interventions by renal denervation and atipamezole resulted in amelioration of the histological findings. Overexpression of TGF-ß1 gene in kidneys of Atg -/- mice was altered in a manner linked to the histological findings. Surprisingly, aliskiren reduced α2-AR gene expression, interstitial fibrosis, and arterial hypertrophy in kidneys of Atg -/- mice, which lack renin substrate. CONCLUSIONS: Alpha2-AR signaling is one of the causes of persistent renal arterial hypertrophy in Atg -/- mice. Aliskiren also angiotensinogen-independently reduces the extent of renal arterial hypertrophy, partly thorough downregulation of α2-ARs. Although renal arterial hypertrophy in Atg -/- mice appears to be of multifactorial origin, TGF-ß1 may play a key role in the persistence of such hypertrophy.

Involvement of the apelin receptor APJ in Fas-induced liver injury.

BACKGROUND: Apelin-APJ signalling is known to play important roles in heart physiology and pathology; however, its functions in liver physiology and pathology remain unclear. On the other hand, Fas is an important molecule in hepatitis and other liver disease that belongs to the death receptor family. The aim of this study was to assess the relationship between apelin-APJ signaling and Fas-mediated liver injury in mice. METHODS: APJ(-/-) mice and wild type (WT) mice were administered an intraperitoneal injection of an agonistic anti-Fas antibody (clone; Jo2), and sacrificed after 3 or 6 h to assess the liver histology. The expression levels of apelin and APJ, plasma levels of transaminases, activities of hepatic caspases and activations of stress-activated protein kinases were also analysed. RESULTS: Before the Jo2 injection, APJ was weakly expressed in the hepatocytes in spots; on the other hand, after the Jo2 injection, it had spread into whole hepatocytes. Moreover, the mRNA expression level of apelin and APJ in the liver increased after Jo2 injection. In the APJ(-/-) mice, the liver injuries and apoptotic changes were significantly inhibited as compared with those in the WT mice. Dramatic increase in JNK activation was observed in the WT mice after Jo2 injection, whereas such activation was completely absent in the APJ(-/-) mice. JNK inhibitor partially, but significantly suppressed Jo2-mediated liver injury in WT mice. CONCLUSION: Apelin-APJ signalling may promote Fas-induced liver injury at least partially via JNK activation, and may thus serve as a potential therapeutic target in cases of acute liver injury.

Influence of pretreatment with H2 receptor antagonists on the cure rates of Helicobacter pylori eradication.

BACKGROUND: Pretreatment with a proton pump inhibitor (PPI) reportedly decreases the efficacy of Helicobacter pylori (H. pylori) eradication, however, the effect of pretreatment with an H2 receptor antagonist (H2RA) on H. pylori eradication has not yet been studied. We compared the efficacy of eradication regimen (lansoprazole/amoxicillin/clarithromycin) in patients with H. pylori infection with or without H2RA pretreatment. MATERIAL/METHODS: In this retrospective study conducted at three centers, 310 patients with H. pylori infection were treated. The diagnosis of H. pylori infection was made using the rapid urease test, bacterial cultures and histological examination of endoscopic biopsy specimens. The patients were assigned to receive an eradication regimen first or following pretreatment with H2RA. Eradication was assessed using the 13C-urea breath test more than 4 weeks after the completion of therapy. RESULTS: Overall, H. pylori was eradicated in 79.7% of the cases: the eradication rate was 81.6% in the pretreatment group, and 77.6% in the eradication first group (p=0.3799, chi-square test). No significant difference in the eradication rate was observed between the two groups. CONCLUSIONS: Pretreatment with H2RA had no significant influence on the efficacy of H. pylori eradication therapy.

Early complications following percutaneous endoscopic gastrostomy: results of use of a new direct technique.

BACKGROUND/AIMS: Percutaneous endoscopic gastrostomy is the standard method for enteral feeding in patients predicted to require long-term enteral nutrition because of dysphagia. A direct techinique with gastropexy is available, in which oropharyngeal passage of the internal bumper can be avoided. The aim of this study was to assess the early complications of percutaneous endoscopic gastrostomy performed using the new direct technique. METHODOLOGY: Between August 2005 and July 2009, 231 patients underwent percutaneous endoscopic gastrostomy at our hospital. We analyzed the clinical characteristics of the patients related to the development of early complications such as bleeding or local infection. Early complications were defined as complications occurring within 7 days of the percutaneous endoscopic gastrostomy. RESULTS: The study population comprised 231 patients: 157 men and 74 women (median age, 73 years; range, 28-92 years). The percutaneous endoscopic gastrostomy was performed using the pull-through technique in 134 of these patients (58%), whereas the direct technique with gastropexy was employed in the remaining 97 patients (42%). In the multiple logistic regression analyses, only the use/non-use of the direct technique was identified as a variable significantly associated with the incidence of bleeding (odds ratio 5.236, 95% confidence interval 1.040-26.316; p = 0.0447) and the incidence of local infection (odds ratio 0.283, 95% confidence interval 0.100-0.802; p = 0.0175). CONCLUSIONS: Use of the direct technique for performing percutaneous endoscopic gastrostomy was associated with the increased incidence of the early complication of bleeding, but the decreased incidence of local infection.

Does pretreatment with proton pump inhibitors influence the eradication rate of Helicobacter pylori?

BACKGROUND/AIMS: Pretreatment with a proton pump inhibitor (PPI) has been reported to decrease the efficacy of Helicobacter pylori (H. pylori) eradication. We compared the efficacy of an eradication regimen (lansoprazole/amoxicillin/clarithromycin) first or following pretreatment with a PPI. METHODOLOGY: In this retrospective study conducted at three centers, 353 patients infected with H. pylori were treated. The H. pylori status was determined using the rapid urease test, bacterial cultures, and the histological examination of endoscopic biopsy specimens, The patients were assigned to receive an eradication regimen first or following pretreatment with a PPI. Eradication was assessed using the 13C-urea breath test more than 4 weeks after the completion of therapy. RESULTS: Overall, H. pylori was eradicated in 78.8% of the cases: 79.6% in the pretreatment group, and 77.6% in the eradication first group (p = 0.6541 by chi square test). No significant difference in the eradication rates was observed between the two groups. CONCLUSIONS: This retrospective study indicated that pretreatment with a PPI does not significantly reduce the efficacy of eradication therapy in patients infected with H. pylori.

Urinary oxidative stress markers closely reflect the efficacy of candesartan treatment for diabetic nephropathy.

BACKGROUNDS/AIMS: It has been reported that urinary oxidative stress markers are higher in diabetic patients with proteinuria. We performed the present study to elucidate the relationship between urinary excretion of oxidative stress markers, albumin excretion, and histological changes, and to confirm the potential utility of oxidative stress markers for clinical treatment. METHODS: Diabetic db/db mice or nondiabetic db/m mice were administered candesartan (10 mg/kg/day) or hydralazine (50 mg/kg/day) for 18 weeks. RESULTS: Thirty-week-old male db/db mice treated with control vehicle revealed elevated urinary excretion and immunohistological levels of 8-hydroxydeoxyguanosine in glomeruli when compared to db/m mice. Treatment with candesartan, but not hydralazine, reduced these values to levels in db/m mice. Increased mesangial expansion, urinary excretion of albumin and 8-isoprostane, and glomerular immunohistological levels of nitrotyrosine in db/db mice were also decreased markedly by candesartan but not hydralazine. Interestingly, correlations between levels of albumin and oxidative stress markers in urine were very high, even when groups undergoing long-term (44 weeks) treatment were included (correlation coefficient 0.767 with respect to 8-hydroxydeoxyguanosine, 0.888 with respect to 8-isoprostane). CONCLUSION: It is anticipated that urinary concentrations of oxidative stress markers will be direct barometers of glomerulus-derived oxidative stress and glomerular injury in diabetic nephropathy.

Gastroesophageal reflux disease in hemodialysis patients.

BACKGROUND: The association between gastroesophageal reflux disease (GERD) and chronic renal failure (CRF) remains unclear. The aim of the present study is to assess the prevalence of GERD and also attempt to identify possible pathogenic factors in the development of reflux in hemodialysis (HD) patients. PATIENTS AND METHODS: This study consisted of 418 stable CRF patients who underwent HD and did not necessarily undergo gastroendoscopy. Instead of gastroendoscopy, QUEST, a structured questionnaire for the assessment of symptomatic GERD, was used to diagnose GERD. We checked the age, sex, body mass index, etiology of renal disease, QUEST score, medication, alcohol consumption, smoking and laboratory data, and compared GERD group with non-GERD group. RESULTS: In the 418 stable CRF patients who did not undergo gastroendoscopy, the prevalence of GERD was 24.2%. There were no statistically significant differences in age, sex, BMI, alcohol consumption, smoking, etiology of CRF, laboratory data and medication between GERD group and non-GERD group. CONCLUSIONS: Compared to the reported prevalence of GERD in Japan (16.3%), the prevalence of GERD in CRF patients who underwent HD (24.2%), was increased. The risk factor for this increased GERD in CRF patients was not clear in the present study.

Gastroesophageal reflux disease in chronic renal failure patients: evaluation by endoscopic examination.

BACKGROUND: The association between gastroesophageal reflux disease (GERD) and chronic renal failure (CRF) remains unclear. The aim of the present study is to assess the gastroendoscopic findings and the prevalence of GERD in CRF patients by endoscopic examination. PATIENTS AND METHODS: This study consisted of 156 CRF patients (97 men and 59 women, mean age: 64.2 years) whose creatinine level was more than 2 mg/dl and who underwent endoscopic examination. We checked their renal function, gastrointestinal symptoms and gastroendoscopical findings, and examined the relationship between renal function and gastroendoscopic findings, and the prevalence of GERD. RESULTS: In the gastroendoscopic findings of the 156 CRF patients who underwent endoscopic examination, the prevalence of GERD was 34.0%. Especially, in symptomatic cases, the prevalence of GERD was 44.0%. In hemodialysis patients, the prevalence of GERD was 50.0%. The prevalence of GERD tended to increase as renal function become worse. There were statistically significant differences between the patients on hemodialysis and pre-dialysis in the prevalence of GERD (P < 0.01). The severity of GERD tended to be mild. CONCLUSIONS: Compared to the reported prevalence of GERD in 6010 Japanese adults (16.3%), the prevalence of GERD in CRF patients, especially who underwent hemodialysis (50.0%), was increased.

Requirement of apelin-apelin receptor system for oxidative stress-linked atherosclerosis.

The recently identified endogenous peptide apelin and its specific apelin receptor (APJ) are currently being considered as potential regulators in vascular tissue. Previously, we reported apelin mediates phosphorylation of myosin light chain and elicits vasoconstriction in vascular smooth muscle. In this study, physiological roles of the apelin-APJ system were investigated on atherosclerosis. In APJ and apolipoprotein E double-knockout (APJ(-/-)ApoE(-/-)) mice fed a high-cholesterol diet, atherosclerotic lesions were dramatically reduced when compared with APJ(+/+) ApoE(-/-) mice, in the absence of an effect of cholesterol levels. Immunohistochemical detection of smooth muscle cells, using a smooth muscle alpha-actin antibody, showed greatly reduced staining for these cells in lesions of APJ(-/-)ApoE(-/-) mice fed a high-cholesterol diet. Vascular production of superoxide radicals and the expression of nicotinamide-adenine dinucleotide phosphate oxidase subunits were decreased in APJ(-/-)ApoE(-/-) mice compared with APJ(+/+)ApoE(-/-) mice fed a standard normal diet. In vascular smooth muscle cells, apelin induced nicotinamide-adenine dinucleotide phosphate oxidase subunit expression. Apelin also induced vascular smooth muscle cell proliferation, which was inhibited by superoxide dismutase or diphenylene iodonium. The apelin-APJ system is a mediator of oxidative stress in vascular tissue, and thus we propose it to be a critical factor in atherogenesis under high-cholesterol dietary conditions. APJ deficiency is preventative against oxidative stress-linked atherosclerosis.