Involvement of aldosterone and mineralocorticoid receptors in rat mesangial cell proliferation and deformability

We demonstrated recently that chronic administration of aldosterone to rats induces glomerular mesangial injury and activates mitogen-activated protein kinases including extracellular signal-regulated kinases 1/2 (ERK1/2). We also observed that the aldosterone-induced mesangial injury and ERK1/2 activation were prevented by treatment with a selective mineralocorticoid receptor (MR) antagonist, eplerenone, suggesting that the glomerular mesangium is a potential target for injuries induced by aldosterone via activation of MR. In the present study, we investigated whether MR is expressed in cultured rat mesangial cells (RMCs) and involved in aldosterone-induced RMC injury. MR expression and localization were evaluated by Western blotting analysis and fluorolabeling methods. Cell proliferation and micromechanical properties were determined by [3H]-thymidine uptake measurements and a nanoindentation technique using an atomic force microscope cantilever, respectively. ERK1/2 activity was measured by Western blotting analysis with an anti-phospho-ERK1/2 antibody. Protein expression and immunostaining revealed that MR was abundant in the cytoplasm of RMCs. Aldosterone (1 to 100 nmol/L) dose-dependently activated ERK1/2 in RMCs with a peak at 10 minutes. Pretreatment with eplerenone (10 micromol/L) significantly attenuated aldosterone-induced ERK1/2 phosphorylation. Aldosterone (100 nmol/L) treatment for 30 hours increased [3H]-thymidine incorporation and decreased the elastic modulus, indicating cellular proliferative and deforming effects of aldosterone, respectively. These aldosterone-induced changes in cellular characteristics were prevented by pretreatment with eplerenone or an ERK (MEK) inhibitor, PD988059 (100 micromol/L). The results indicate that aldosterone directly induces RMC proliferation and deformability through MR and ERK1/2 activation, which may contribute to the pathogenesis of glomerular mesangial injury.     

Cytomegalovirus cholangitis and pancreatitis in an immunocompetent patient

Cholangitis and pancreatitis associated with cytomegalovirus (CMV) infection in an immunocompetent patient is reported. Endoscopic retrograde cholangiography performed on a 55-year-old man for evaluation of the cause of jaundice and liver dysfunction revealed a distal focal irregular narrowing of the common bile duct. Microscopic findings of the resected specimen showed chronic cholangitis and CMV pancreatitis. Immunohistochemistry disclosed that epithelial cells in the inflamed bile duct were positive for CMV antigen, which was compatible with CMV cholangitis. Inflammation of the biliary tract or pancreas by CMV has been commonly reported as a complication in immunocompromised patients. Our report appears to be a rare case, but suggests that CMV cholangitis or pancreatitis should be considered in the differential diagnoses of common bile duct stenosis or pancreatitis even in immunocompetent individuals.     

Effects of local administrations of tempol and diethyldithio-carbamic on peripheral nerve activity

We have recently shown that systemic administration of a superoxide dismutase mimetic, tempol, resulted in decreases in mean arterial pressure and heart rate along with a reduction in renal sympathetic nerve activity (RSNA). It has also been shown that these parameters are significantly increased by systemic administration of a superoxide dismutase inhibitor, diethyldithio-carbamic (DETC), indicating a potential role of reactive oxygen species in the regulation of RSNA. In this study, we examined the effects of local administrations of 4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl (tempol) and DETC on RSNA in anesthetized rats. Either tempol or DETC was directly administered onto the renal sympathetic nerves located between the electrode and ganglion. Local application of tempol (10 microL, 0.17 to 1.7 mol/L, n=6) resulted in dose-dependent decreases in integrated RSNA (by -81+/-6% at 1.7 mol/L) without alterations in mean arterial pressure and heart rate. In contrast, DETC (10 microL, 0.17 to 1.7 mol/L, n=6) increased RSNA dose-dependently. The responses of RSNA to tempol and DETC were significantly greater in spontaneously hypertensive rats than in normotensive rats (n=6, respectively). Local application of sodium nitroprusside (1 mmol/L) or N(G)-nitro-L-arginine methyl ester (0.11 mol/L) altered neither basal RSNA nor tempol-induced reductions in RSNA (n=6 and 5, respectively). A voltage-gated potassium channel blocker, 4-aminopyridine (0.1 mol/L), significantly decreased basal RSNA (by -81+/-1%) and completely prevented DETC-induced increases in RSNA (n=5). These results suggest that reactive oxygen species play a role in the regulation of peripheral sympathetic nerve activity, and that at least part of this mechanism is mediated through voltage-gated potassium channels.     

A case of metastatic liver tumor from colorectal carcinoma--continued arterial infusion chemotherapy through a microcatheter located in replaced right hepatic artery

The patient was a 78-year-old male with a history of colon cancer. After surgical resection of colon cancer, he suffered a multiple liver metastasis. We treated him by arterial infusion chemotherapy with the catheter edge embedded at the common hepatic artery. For a long period, the lesions were defined as partial response on WHO-criteria, but a wide area of the common hepatic artery was shrunk. After changing the treatment to systemic intravenous chemotherapy, the metastatic lesions began to enlarge. Then, we somehow were able to put a microcatheter into the replaced right hepatic artery (rRHA), and could restart arterial infusion chemotherapy. We continued this procedure for over a year without any complication.     

A case responding to weekly paclitaxel (TXL) therapy as third line chemotherapy for scirrhous type gastric cancer

A 67-year-old female was admitted to our hospital in May, 2001 for examination. She was diagnosed with advanced gastric cancer that was inoperable due to peritoneal dissemination. Seventeen courses of sequential MTX and 5-FU therapy, and 2 courses of TS-1 plus CDDP were carried out. A partial response (PR) and prolonged NC were obtained after these chemotherapies. However, pleural effusion and ascites appeared again, and we diagnosed progressive disease. As a third line chemotherapy for this patient, paclitaxel (TXL) was administered. Treatment consisted of two 3-week courses of paclitaxel 70 mg per m2 on day 1 of each week, with a 1-week break between the courses. Two weeks after the start of this therapy, pleural effusion and ascites had completely disappeared. Paclitaxel is considered to be promising for advanced gastric cancers, as second or third line chemotherapy with paclitaxel for patients with inoperable gastric cancer seems to be effective in improving QOL.     

PEDUNCULATED GASTRIC SIGNET RING CELL CARCINOMA

Signet ring cell carcinoma (SRCC) is characterized by poor ductal formation and a diffuse progression pattern and generally presents as a depressed lesion in the majority of cases. We describe here an extremely rare case of gastric SRCC that presented as a pedunculated lesion. We hypothesize that the major factor responsible for the elevation of this lesion was proliferation of signet ring cells that did not lose their mutual connections. Among the two cases of early elevated‐type gastric SRCC that have been reported in the literature, this is the first case of pedunculated intramucosal SRCC. Pathological examination revealed no cancer cells in the basal part of the elevated lesion. The cellular morphology was consistent with SRCC, although the ductal structure was well preserved and more similar to well‐differentiated adenocarcinoma. Endoscopic examination showed a smooth‐surfaced lesion with no depressed region around the basal part of the elevated lesion. Because these findings differ significantly from previous reports of elevated SRCC, this report provides further insight into the nature of SRCC.     

Pedunculated carcinoid tumor of the gallbladder--analysis of the relationship between location and morphology in carcinoid tumor of the gallbladder]

Laparoscopic cholecystectomy was performed in a 54-year-old man because of gallbladder neck cancer suspected on endoscopic ultrasonography and computed tomography. The pathological diagnosis was carcinoid tumor of the gallbladder. Our case had the pedunculated morphology which was distinguishing characteristic. We analyzed the relationship between location and morphology in previously reported cases of gallbladder carcinoid tumor in Japan. The result indicated that carcinoid tumor of the gallbladder neck became pedunculated or subpedunculated more frequently than in the rectum or stomach.     

Possible contributions of reactive oxygen species and mitogen-activated protein kinase to renal injury in aldosterone/salt-induced hypertensive rats

Studies were performed to test the hypothesis that reactive oxygen species (ROS) and mitogen-activated protein kinase (MAPK) contribute to the pathogenesis of aldosterone/salt-induced renal injury. Rats were given 1% NaCl to drink and were treated with one of the following combinations for 6 weeks: vehicle (0.5% ethanol, SC, n=6); aldosterone (0.75 microg/H, SC, n=8); aldosterone plus a selective mineralocorticoid receptor antagonist; eplerenone (0.125% in chow, n=8); aldosterone plus an antioxidant; and tempol (3 mmol/L in drinking solution, n=8). The activities of MAPKs, including extracellular signal-regulated kinases (ERK)1/2, c-Jun-NH2-terminal kinases (JNK), p38MAPK, and big-MAPK-1 (BMK1) in renal cortical tissues were measured by Western blot analysis. Aldosterone-infused rats showed higher systolic blood pressure (165+/-5 mm Hg) and urinary excretion of protein (106+/-24 mg/d) than vehicle-infused rats (118+/-3 mm Hg and 10+/-3 mg/d). Renal cortical mRNA expression of p22phox, Nox-4, and gp91phox, measured by real-time polymerase chain reaction, was increased in aldosterone-infused rats by 2.3, 4.3, and 3.0-fold, respectively. Thiobarbituric acid-reactive substances (TBARS) content in renal cortex was also higher in aldosterone (0.23+/-0.02) than vehicle-infused rats (0.09+/-0.01 nmol/mg protein). ERK1/2, JNK, and BMK1 activities were significantly elevated in aldosterone-infused rats by 3.3, 2.3, and 3.0-fold, respectively, whereas p38MAPK activity was not changed. Concurrent administration of eplerenone or tempol to aldosterone-infused rats prevented the development of hypertension (127+/-2 and 125+/-5 mm Hg), and the elevations of urinary excretion of protein (10+/-2 and 9+/-2 mg/day) or TBARS contents (0.08+/-0.01 and 0.11+/-0.01 nmol/mg protein). Furthermore, eplerenone and tempol treatments normalized the activities of ERK1/2, JNK, and BMK1. These data suggest that ROS and MAPK play a role in the progression of renal injury induced by chronic elevations in aldosterone.