Bcl-2-modifying factor induces renal proximal tubular cell apoptosis in diabetic mice

This study investigated the mechanisms underlying tubular apoptosis in diabetes by identifying proapoptotic genes that are differentially upregulated by reactive oxygen species in renal proximal tubular cells (RPTCs) in models of diabetes. Total RNAs isolated from renal proximal tubules (RPTs) of 20-week-old heterozygous db/m+, db/db, and db/db catalase (CAT)-transgenic (Tg) mice were used for DNA chip microarray analysis. Real-time quantitative PCR assays, immunohistochemistry, and mice rendered diabetic with streptozotocin were used to validate the proapoptotic gene expression in RPTs. Cultured rat RPTCs were used to confirm the apoptotic activity and regulation of proapoptotic gene expression. Additionally, studies in kidney tissues from patients with and without diabetes were used to confirm enhanced proapoptotic gene expression in RPTs. Bcl-2-modifying factor (Bmf) was differentially upregulated (P<0.01) in RPTs of db/db mice compared with db/m+ and db/db CAT-Tg mice and in RPTs of streptozotocin-induced diabetic mice in which insulin reversed this finding. In vitro, Bmf cDNA overexpression in rat RPTCs coimmunoprecipated with Bcl-2, enhanced caspase-3 activity, and promoted apoptosis. High glucose (25 mmol/L) induced Bmf mRNA expression in RPTCs, whereas rotenone, catalase, diphenylene iodinium, and apocynin decreased it. Knockdown of Bmf with small interfering RNA reduced high glucose-induced apoptosis in RPTCs. More important, enhanced Bmf expression was detected in RPTs of kidneys from patients with diabetes. These data demonstrate differential upregulation of Bmf in diabetic RPTs and suggest a potential role for Bmf in regulating RPTC apoptosis and tubular atrophy in diabetes.     

Radikale Zystektomie – pro laparoskopisch

Although the technical feasibility of laparoscopic radical cystectomy (LRC) has been proven and the procedure has been accepted in the EAU guidelines 2011 as a valid alternative, its actual position has to be determined. On the one hand the advantages of LRC (less blood loss, lower transfusion rates, shorter analgesia time) have been proven in retrospective studies; however, the technical difficulties of purely laparoscopic urinary diversion result in very long operating times and in cases of a laparoscopic-assisted creation of a neobladder, the question of the advantage of this approach remains doubtful. Despite case reports of port metastases and peritoneal carcinosis following laparoscopic and robot-assisted radical cystectomy, there is no difference in terms of oncological long-term data (up to 10 years) between laparoscopy and open surgery performed at centres of excellence. Evidently, the curative options for the patients do not depend on the type of surgery (open versus minimally invasive) but on the efficacy of adjuvant treatment strategies (polychemotherapy). Currently it is believed that LRC should be considered for patients with low risk of progression (pT1-2). The final position of laparoscopic radical cystectomy can only be evaluated in a multicentric randomized controlled trial.     

N-methylation of phenylpyridines and bispyridyls as a potential toxication route: tissue distribution of azaheterocycle N-methyltransferase activity in the rabbit

The in vitro N-methylating capability of rabbit tissue cytosolic preparations, utilizing S-adenosyl-L-[methyl-3H]methionine as methyl donor, is described. Dialysed preparations from the lung, liver and kidney are capable of N-methylating 3- and 4-phenylpyridines and 3,3'- and 4,4'-bispyridyls; the corresponding 2-substituted derivatives are not substrates. With all the four substrates, azaheterocycle N-methyltransferase activity decreased in the order lung greater than kidney greater than liver; the activity in the lung was manifold greater than in the kidney and the liver. Azaheterocycle N-methyltransferase activity could not be detected in the brain cytosol under the enzyme assay conditions used. The production of N-methylpyridinium ion metabolites in the lung, from 4-phenylpyridine, 4,4'-bispyridyl and other pyridino-compounds present in tobacco smoke, may contribute to the observed pulmonary toxicity in tobacco users.