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Abstract: The pathogenesis of ischemia-reperfusion (I/R) injury is known to involve cytokines and particularly surface adhesion molecules, the expression of which initiates the attachment of inflammatory cells. Renal I/R injury, a clinically important problem, is an invariable consequence of renal transplantation. The problem begins at the onset of acute tubular necrosis (ATN), when the transplantation includes a long ischemic interval or by use of a cardiac arrest donor''s kidney. The cysteinyl leukotriene-1 (CysLT1), a potent lipid mediator in allergic disease, acts through the CysLT1R receptor. We researched the expression of CysLT1R in rat renal I/R injury as well as correlations with the degree of ATN. The right kidney was harvested and the left renal artery and vein were clamped at laparotomy. The kidney was reperfused after 90 minutes of ischemia; rats were sacrificed at 0, 3, 5, 12, and 24 hours after reperfusion. CysLT1R expression was analyzed by immunohistochemistry. CysLT1R expression was observed only in endothelial cells of a normal kidney. CysLT1R expression was most intense on endothelial cells at 3 hours after reperfusion, and CysLT1R expression on endothelial cells gradually became weaker. Twelve hours after reperfusion, ATN extended throughout the ischemic kidney. Renal I/R injury gradually progressed at time after reperfusion. Several hours after the maximal CysLT1R expression, we observed the maximum renal I/R injury. [Copyright &y& Elsevier]

In 2012, bixalomer was launched as new non-calcium (Ca) containing phosphorus (P) binder, increasing the choices available for the treatment of hyperphosphatemia. In this study, among the maintenance dialysis patients at our hospital, we newly administered bixalomer to 21 patients who were not receiving any P binders, and switched to bixalomer for 13 patients who had been receiving sevelamer hydrochloride and 23 patients who had been receiving lanthanum carbonate. The initial dosage of bixalomer was set as 1500 mg/day for new administration patients and dosage equivalent to that of the previously-used P binder for patients who were switched to bixalomer. The dosage of bixalomer was increased if the effects were insufficient. The serum P, Ca and intact parathyroid hormone concentrations as well as serum pH, HCO3 concentration and base excess were evaluated prior to administering bixalomer, 3 months and 6 months after administering bixalomer. For the group who were newly administered bixalomer, significant reductions in serum P concentrations were seen (P<0.01) and no significant changes were seen in clinical test items that serve as indices for acidosis. For the group who were switched from sevelamer hydrochloride to bixalomer, significant reductions in serum P concentrations were seen (P<0.01) together with significant improvements in acidosis (P<0.01). For the group who were switched from lanthanum carbonate to bixalomer, by increasing the dosage of bixalomer to approximately three times the dosage of lanthanum carbonate, it was possible to maintain post-switch serum P concentrations at almost the same levels as before the switch. Furthermore, there were minor, yet significant improvements in acidosis (P<0.01). From these results, it was shown that bixalomer can be useful treatment alternative in dialysis patients for whom it is necessary to change the P binder due to insufficient management of serum P concentrations or development of acidosis., (© 2014 The Authors. Therapeutic Apheresis and Dialysis © 2014 International Society for Apheresis.)

Angiotensin II receptor blockers (ARBs) are widely used as hypertensive therapeutic agents. In addition, studies have provided evidence that ARBs have the potential to inhibit the growth of several types of cancer cells. It was reported that telmisartan (a type of ARB) has peroxisome proliferator-activated receptor (PPAR)-γ activation activity. We previously reported that the PPAR-γ ligand induces growth arrest in human urological cancer cells through apoptosis. In this study, we evaluated the effects of telmisartan and other ARBs on cell proliferation in renal cell carcinoma (RCC), bladder cancer (BC), prostate cancer (PC) and testicular cancer (TC) cell lines. The inhibitory effects of telmisartan and other ARBs (candesartan, valsartan, irbesartan and losartan) on the growth of the RCC, BC, PC and TC cell lines was investigated using an MTT assay. Flow cytometry and Hoechst staining were used to determine whether the ARBs induced apoptosis. Telmisartan caused marked growth inhibition in the urological cancer cells in a dose- and time-dependent manner. Urological cancer cells treated with 100 μM telmisartan underwent early apoptosis and DNA fragmentation. However, the other ARBs had no effect on cell proliferation in any of the urological cancer cell lines. Telmisartan may mediate potent anti-proliferative effects in urological cancer cells through PPAR-γ. Thus, telmisartan is a potent target for the prevention and treatment of human urological cancer.

Sphingosine-1 phosphate receptor (S1PR) has come to the fore as a mediator of extracellular signaling through its interaction with G-protein-coupled receptors, which results in the induction of peripheral T-cell depletion. The mechanisms involved in renal ischemia-reperfusion (I/R) injury are complex, but appear to involve the early participation of bone marrow-derived cells, such as T lymphocytes. In this study, we investigated the expression of SIPR in a rat model of renal I/R injury. By means of a laparotomy, the right kidney was harvested and the left renal artery and vein were clamped. The kidney was reperfused after 90 min of ischemia, and rats were sacrificed at 0, 3, 6, 12 and 24 h after reperfusion. S1PR expression was analyzed by immunohistochemistry, and was observed only in endothelial cells of the normal kidneys. From 0 to 3 h after reperfusion, S1PR expression gradually became stronger in endothelial cells, reaching its peak intensity at 3 h after reperfusion. Twelve hours after reperfusion, necrosis had extended throughout the ischemic kidney, and nearly all the tubular epithelial cells had been destroyed. From 3 to 12 h after reperfusion, S1PR expression gradually weakened. At 24 h after reperfusion, levels of S1PR expression had almost reached those of the normal kidneys. In conclusion, S1PR was found to be expressed in a rat model of renal I/R injury. Several hours after achieving the maximum level of S1PR expression, the maximum level of renal I/R injury was observed. These results suggest a relationship between S1PR and renal I/R injury.

Recent studies have demonstrated that the cysteinyl-leukotriene1 receptor (CysLT1R) antagonist induces the growth arrest of cancer cells through apoptosis. In this study, we examined the effects of the CysLT1R antagonist on cell proliferation in urological cancer cell lines, including renal cell carcinoma, bladder cancer, prostate cancer and testicular cancer cells. The inhibitory effect of the CysLT1R antagonist on the urological cancer cells was investigated using the MTT assay and flow cytometry. The CysLT1R antagonist induced a reduction in cell viability with a half-maximal concentration of growth inhibition in all the urological cancer cell lines, and arrested the growth of the cells through early apoptosis. In conclusion, the CysLT1R antagonist may mediate potent anti-proliferative effects against urological cancer cells through early apoptosis, and may therefore serve as a novel therapeutic target in the treatment of urological cancer.

Objectives: To investigate the leukotriene (LT) D(4) (LTD(4)) receptor (cysteinyl-LT(1) receptor [CysLT(1)R]) expression in transitional cell carcinoma (TCC) of the bladder, as well as the effects of the CysLT(1)R antagonist on cell proliferation in TCC cell lines. The metabolism of arachidonic acid by either cyclooxygenase or lipoxygenase is thought to play an important role in carcinogenesis. LTD(4) is a pro-inflammatory mediator derived from arachidonic acid through various enzymatic steps, and 5-lipoxygenase is an important factor in generating LTD(4)., Methods: CysLT(1)R expression in TCC tissue and normal bladder tissue was examined. CysLT(1)R expression was detected using immunohistochemistry. The effects of the CysLT(1)R antagonist on TCC cell growth were examined by 3-(4,5-dimethylthiazol-2-thiazolyl)-2,5-diphenyltetrazolium bromide assay and reverse transcriptase-polymerase chain reaction. Flow cytometry was used to determine whether the CysLT(1)R antagonist induced apoptosis., Results: Initially, only slight CysLT(1)R expression was detected in normal bladder tissues and marked CysLT(1)R expression was detected in the TCC tissues. CysLT(1)R expression was greater in high-grade cancer than in low-grade cancer. Furthermore, CysLT(1)R expression was also greater in advanced-stage cancer than in early-stage cancer. Finally, the CysLT(1)R antagonist caused marked inhibition of TCC cells by inducing early apoptosis., Conclusions: CysLT(1)R was induced in TCC. The results suggest that the CysLT(1)R antagonist might mediate potent antiproliferative effects on TCC cells. Thus, the target of the CysLT(1)R is potentially a new therapy in the treatment of TCC.

The metabolism of arachidonic acid by either cyclooxygenase or lipoxygenase is believed to play an important role in carcinogenesis. Leukotriene (LT) D4 is a pro-inflammatory mediator derived from arachidonic acid through various enzymatic steps, and 5-lipoxygenase is an important factor in generating LTD4. We investigated LTD4 receptor (cysteinylLT1 receptor; CysLT1R) expression in testicular cancer (TC), as well as the effects of the CysLT1R antagonist on cell proliferation in a TC cell line. CysLT1R expression in tissue from TC patients and normal testes (NTs) was detected using immunohistochemistry and RT-PCR. The effects of the CysLT1R antagonist on TC cell growth were examined using the MTT assay. Flow cytometry was used to determine whether or not the CysLT1R antagonist induces apoptosis. Immunohistochemistry indicated that CysLT1R expression was strong in all types of TC tissues, but very weak in NT tissues. The TC cell line expressed CysLT1R mRNA as detected by RT-PCR. MTT and flow cytometry revealed that the CysLT1R antagonist caused marked inhibition of TC cells through early apoptosis. In conclusion, CysLT1R was induced in TC. The results suggest that the CysLT1R antagonist may mediate potent anti-proliferative effects against TC cells. Thus, CysLT1R may become a new therapeutic target for the treatment of TC.

Angiotensin II receptor blockers (ARBs) are widely used as hypertensive therapeutic agents. However, it has been reported that Telmisartan (a type of ARB) additionally activates peroxisome proliferator-activated receptor (PPAR)-γ. We previously reported that PPAR-γ ligand induced the growth arrest of renal cell carcinoma (RCC) cells through apoptosis, and that Telmisartan had the potential to inhibit prostate cancer cell growth through apoptosis. In this study, we evaluated the effects of Telmisartan and other ARBs on cell proliferation in an RCC cell line using normal proximal tubular endothelial cells (PRTECs) and the human RCC (Caki-1) cell line. The effects of Telmisartan as well as of other ARBs (Candesartan, Valsartan, Irbesartan and Losartan) on RCC cell growth were examined by MTT assay. Flow cytometry and Hoechst staining were used to determine whether or not the ARBs induced apoptosis. Telmisartan caused marked inhibition in RCC cells in a concentration- and time-dependent manner. Treatment with 100 µM of Telmisartan induced early apoptosis and DNA fragmentation in the RCC cells, but not in the PRTECs. None of the other ARBs had an effect on cell proliferation in the RCC cells or the PRTECs. Telmisartan may mediate potent antiproliferative effects against RCC cells through PPAR-γ. Thus, Telmisartan is a potential target for prevention and treatment in RCC.

Angiotensin II receptor blockers (ARBs) are widely used as hypertensive therapeutic agent. Recent studies have reported that ARBs have the potential to inhibit the growth of prostate cancer (PC) cells. Moreover, it was recently reported that Telmisartan (a kind of ARB) has peroxisome proliferator-activated receptor (PPAR)-gamma activation. We previously reported that PPAR-gamma ligand induces growth arrest of PC cells through apoptosis. In this study, we evaluated the effects of the Telmisartan and other ARBs on cell proliferation in several PC cell lines. We used normal prostate stromal cell (NPC), human hormone-refractory PC (PC3), androgen-independent PC (DU-145) and androgen-dependent PC (LNCaP) cell lines. Effects of Telmisartan and other ARBs (Candesartan, Valsartan, Irbesartan and Losartan) on PC cell growth were examined by MTT assay. Flow cytometry and Hoechst staining were used to determine whether or not ARBs induce apoptosis. Telmisartan caused marked inhibition of PC cells in concentration-dependent and time-dependent manner. PC cells with treatment of 100 microM Telmisartan induced early apoptosis and DNA fragmentation. However, NPC with treatment of 100 microM Telmisartan did not induce apoptosis or DNA fragmentation. Furthermore, other ARBs had no effect on cell proliferation in the PC cells and NPC. Telmisartan may mediate potent antiproliferative effects against PC cells through PPAR-gamma. Thus, Telmisartan is a potent target for prevention and treatment in PC.

In renal transplantation, ischemia-reperfusion (I/R) injury is a major cause of renal dysfunction. Activated neutrophils are reported to be closely involved in I/R injury after renal transplantation. Neutrophil elastase, a protease released from activated neutrophils, damages tubular endothelial cells. We investigated the beneficial effect of neutrophil elastase inhibitor (ONO-5046.Na) on renal I/R injury in rats. The study was conducted using 10 male Lewis rats (270-320 g) that were intravenously administered ONO-5046.Na (30 mg/kg before ischemia and after reperfusion) (group A) and control rats (group B) in a 90-min renal warm I/R injury model. Neutrophil elastase expression was analyzed using immunohistochemical staining, and the degree of renal dysfunction was evaluated using H&E staining and blood biochemistry. Neutrophil elastase was detected in tubular endothelial cells. The necrotic area extended to and encompassed nearly all the ischemic kidney within 12 h after reperfusion. The necrotic area and the grade of neutrophil elastase staining were significantly reduced in group A compared to group B. Significant differences in blood urea nitrogen and serum creatinine levels were observed. Survival rates over a 14-day period were examined. No rats survived for more than 4 days in group B. However, 2 of the 10 rats (20%) in group A survived for a 14-day period. To conclude, ONO-5046.Na inhibits neutrophil elastase and reduces acute tubular necrosis. Thus, it is a potent therapeutic agent for the control of renal I/R injury in renal transplantation.

The metabolism of arachidonic acid by either the cyclooxygenase (COX) or the lipoxygenase (LOX) pathway generates eicosanoids, which have been implicated in the pathogenesis of a variety of human diseases, including ischemia-reperfusion (I/R) injury. Several reports have demonstrated that COX-2 and LOX inhibitors can reduce the damage caused by I/R injury. However, few reports have investigated the effects of COX and LOX expression on renal I/R injury, thus this study aimed to do so in a rat renal I/R injury model. The right kidney was harvested and the left renal artery and vein were clamped under laparotomy. The kidney was reperfused after 90 min of ischemia, and rats were sacrificed at 0, 1.5, 3, 5, 12 and 24 h after reperfusion. COX and LOX expression was analyzed by immunohistochemistry. COX-2 and 5- and 12-LOX expression was most intense in the endothelial cells at 3 and 5 h after reperfusion. The expression of COX-2 was stronger than that of 5- and 12-LOX. However, in the hours following reperfusion there were no significant variations in COX-1 expression. Our results demonstrate that COX-2 and LOX can be induced in a rat renal I/R injury model, and that the arachidonic acid pathways play a very important role in renal I/R injury.

The metabolism of arachidonic acid (AA) by either cyclooxygenase or lipoxygenase is believed to play an important role in carcinogenesis. Leukotriene (LT) D4 is a proinflammmatory mediator derived from AA through various enzymatic steps, and 5-lipoxygenase is an important factor in generating LTD4. We investigated LTD4 receptor (cysteinylLT1 receptor, CysLT1R) expression in renal cell carcinoma (RCC), as well as the effect of the CysLT1R antagonist on cell proliferation in the RCC cell line. CysLT1R expression was detected by immunohistochemistry and examined in RCC patients and normal kidney (NK) tissues. The effect of the CysLT1R antagonist on RCC cell growth was examined by MTT assay. Flow cytometry was used to determine whether or not the CysLT1R antagonist induced apoptosis. Initially, only slight CysLT1R expression was detected in NK tissues, and marked CysLT1R expression in RCC tissues. CysLT1R expression was higher in high-grade than in low-grade cancer. Furthermore, the CysLT1R antagonist caused marked inhibition of RCC cells in a concentration- and time-dependent manner through early apoptosis. To conclude, CysLT1R was induced in RCC and the results suggest that the CysLT1R antagonist may mediate the potent anti-proliferative effects of RCC cells. Thus, CysLT1R may become a new target therapy in the treatment of RCC.

The metabolism of arachidonic acid by either cyclooxygenase or lipoxygenase is believed to play an important role in carcinogenesis. Leukotriene (LT) D4 is a proinflammmatory mediator derived from arachidonic acid through various enzymatic steps, and 5-lipoxygenase is an important factor in generating LTD4. We investigated LTD4 receptor (cysteinyl LT1 receptor: CysLT1R) expression in prostate cancer (PC), as well as the effects of CysLT1R antagonist on cell proliferation in PC cell lines. CysLT1R expression in PC patients, prostatic intraepithelial neoplasia (PIN), benign prostatic hyperplasia (BPH), and normal prostate (NP) tissues were examined. CysLT1R expression was detected by immunohistochemistry. Effects of CysLT1R antagonist on PC cell growth were examined by MTT assay. Flow cytometry and Hoechst staining were used to determine whether or not the CysLT1R antagonist induces apoptosis. Initially, only slight CysLT1R expression was detected in BPH and NP tissues and marked CysLT1R expression was detected in PIN and PC tissues. CysLT1R expression was higher in high-grade cancer than in low-grade cancer. Furthermore, CysLT1R antagonist caused marked inhibition of PC cells in a concentration- and time-dependent manner through early apoptosis. In conclusion, CysLT1R is induced in PC, and the results suggest that CysLT1R antagonist may mediate potent anti-proliferative effects of PC cells. Thus, the target of CysLT1R may become a new therapy in the treatment of PC.

This article presents a new transurethral resection (TUR) system for use in endoscopic surgery. By using an electroconductive solution (physiological saline) as the perfusate in lieu of conventional non-electroconductive solution (Uromatic), additional anesthesia (e.g., obturator nerve blocking) is not required. The new TUR is carried out in an electroconductive solution such as saline, and because radiofrequency current flows from the resecting electrode through the perfusate to the outer sheath, no counter-electrode is needed. We have treated both bladder tumor and benign prostatic hyperplasia cases with this new system. Surgery was safely performed in all TUR-bt cases without requiring obturator nerve blocking. During both TUR-bt and transurethral resection of the prostate (TUR-P) using this system, tissue resection and coagulation equivalents were similar to the conventional TUR system. In previous TUR, preoperative obturator nerve blocking was necessary, and in some cases, incomplete blocking or complications occurred. When physiological saline is used as the perfusate, blood electrolyte levels are not greatly changed, even after extensive resection of the bladder wall; as a result, this new system is also cost effective because physiological saline is less expensive than non-electroconductive solutions and requires no counter-electrode. Thus, in comparison with conventional TUR, this new system is both significantly safer and more cost effective.

A case of renal cell carcinoma, found after skin metastasis is presented. A 79-year-old man visited Osaka JR hospital, complaining of a painless nodular mass on his right chest. The mass was resected and histopathological examination revealed a clear cell carcinoma (alveolar type, G1) with no involvement of the mammary gland. Abdominal ultrasound and magnetic resonance imaging revealed a heterogenous lower pole mass in the right kidney. Ultrasound-guided needle biopsy of the right renal mass was performed for histopathological diagnosis, which was clear cell carcinoma (alveolar type, G1). At that time, multiple metastases appeared in bilateral lung fields. The patient is currently receiving interferon-alpha therapy, without surgical treatment.

Purpose: To examine the relationship of the use of calcium channel blockers (CCBs) in hypertensive patients to myocardial infarction in Japan, where CCBs are prescribed much more frequently than in Europe and America., Design: We conducted a nested case-control study using a hospital information system in Japan., Subjects: Cases were hypertensive patients who were repeat visitors to Tokyo University Hospital as of April 1996 and had an incidence of fatal or non-fatal myocardial infarction between 1996 and 1999. Controls were hypertensive patients individually matched to cases by sex, age and history of angina pectoris., Results: The study consisted of 16 cases, who were matched to 80 controls. Of the 80 control patients, 54 (68%) received CCBs. On the other hand, all but one of 16 cases received CCBs and the crude odds ratio of myocardial infarction associated with the use of calcium channel blockers was as high as 7.0 (0.9-55.3). The odds ratio was reduced to 4.9 (0.6-42.4) when adjusted by diabetes and diastolic blood pressure., Conclusions: Although the crude odds ratio of myocardial infarction associated with CCBs was high, the ratio was reduced when adjusted by known confounding factors, suggesting a mechanism of confounding by indication. In addition, the results obtained in this study using records from a single hospital should not be generalized.