[Therapy of inflammatory kidney diseases. More than steroids?]. / Therapie entzündlicher Nierenerkrankungen. Mehr als Steroide?

The term "inflammatory kidney diseases" characterizes primarily immunopathogenetically driven diseases, affecting both kidneys. Bacterial infections, or primarily interstitial nephritis, shall not be considered in this overview. Classification and terminology of inflammatory kidney diseases follow morphological criteria, acuteness of the clinical course, and concomitant organ affection. The clinical course and pathology of inflammatory kidney diseases have been reviewed extensively in this journal in 1997 and 2002.

Regulation of mesangial cell function by vasodilatory signaling molecules.

Proliferation of mesangial cells and expansion of mesangial matrix is a hallmark of glomerular disease leading to end-stage renal failure and requiring renal replacement therapy. Independently from the type of injury, e.g. in glomerulonephritis or diabetic nephropathy, the response to injury is remarkably uniform. Chronic glomerular disease is frequently associated with increases in systemic blood pressure and altered intraglomerular hemodynamics. Furthermore, reduction of systemic blood pressure and inhibition of the vasoconstrictor peptide angiotensin II have been shown to delay end-stage renal failure in various types of human kidney disease. Since vasoconstrictors of mesangial cells and efferent glomerular arterioli, such as angiotensin II, are thought to be detrimental for the progression of chronic glomerular disease, we propose that vasodilatory factors which antagonize the effects of angiotensin II, might have beneficial effects during the course of progressive kidney disease. To support this concept we will summarize currently available data on the role of vasodilatory signaling molecules such as natriuretic peptides (ANP, BNP and CNP), nitric oxide (NO), the prostaglandines PGE2 and prostacycline, and the purine mediator adenosine in the regulation of mesangial function.

[Treatment of arterial traumas by the Wallgraft endoprosthesis]. / Behandlung von iliakalen Gefässverletzungen mittels der Wallgraft-Endoprothese.

PURPOSE: Percutaneous peripheral interventional procedures as well as coronary interventions can be complicated by dissections and traumatic lesions of peripheral arteries. The aim of this study was to evaluate the efficacy of treatment for traumatic peripheral arterial lesions. MATERIAL AND METHODS: In this study we used the Wallgraft-Endoprothesis (Boston Scientific, USA), which is a self-expanding covered stent. In 17 patients a total number of 24 endoprostheses (mean length 6.4 cm) were implanted in iliac arteries. Indications for stenting were large dissections (n = 9), arterial perforations (n = 4), aneurysms (n = 3), and stent in stent implantation (n = 2). RESULTS: An immediate exclusion of the lesion could be achieved in all cases. There were no major procedural complications. The primary patency after a mean follow-up of 18 months was 82.4% (14/17). Early reocclusion was seen in two cases, one stent in stent reocclusion and one reocclusion after acute stent thrombosis. In one other case the angiography revealed relevant restenosis (> 75%). The patency could be restored in one of these three cases leading to a secondary patency rate of 94.1%. CONCLUSIONS: The Wallgraft-Endoprotheses seems to be safe and effective to seal large dissections and traumatic lesions of peripheral arteries, showing a high long-term patency rate.

Peroxidase activity in prostaglandin endoperoxide H synthase-1 occurs with a neutral histidine proximal heme ligand.

Prostaglandin endoperoxide H synthases-1 and -2 (PGHS-1 and -2) convert arachidonic acid to prostaglandin H(2) (PGH(2)), the committed step in prostaglandin and thromboxane formation. Interaction of peroxides with the heme sites in PGHSs generates a tyrosyl radical that catalyzes subsequent cyclooxygenase chemistry. To study the peroxidase reaction of ovine oPGHS-1, we combined spectroscopic and directed mutagenesis data with X-ray crystallographic refinement of the heme site. Optical and Raman spectroscopy of oxidized oPGHS-1 indicate that its heme iron (Fe(3+)) exists exclusively as a high-spin, six-coordinate species in the holoenzyme and in heme-reconstituted apoenzyme. The sixth ligand is most likely water. The cyanide complex of oxidized oPGHS-1 has a six-coordinate, low-spin ferric iron with a v[Fe-CN] frequency at 445 cm(-)(1); a monotonic sensitivity to cyanide isotopomers that indicates the Fe-CN adduct has a linear geometry. The ferrous iron in reduced oPGHS-1 adopts a high-spin, five-coordinate state that is converted to a six-coordinate, low-spin geometry by CO. The low-frequency Raman spectrum of reduced oPGHS-1 reveals two v[Fe-His] frequencies at 206 and 222 cm(-)(1). These vibrations, which disappear upon addition of CO, are consistent with a neutral histidine (His388) as the proximal heme ligand. The refined crystal structure shows that there is a water molecule located between His388 and Tyr504 that can hydrogen bond to both residues. However, substitution of Tyr504 with alanine yields a mutant having 46% of the peroxidase activity of native oPGHS-1, establishing that bonding of Tyr504 to this water is not critical for catalysis. Collectively, our results show that the proximal histidine ligand in oPGHS-1 is electrostatically neutral. Thus, in contrast to most other peroxidases, a strongly basic proximal ligand is not necessary for peroxidase catalysis by oPGHS-1.

Isolation and characterisation of the human rab18 gene after stimulation of endothelial cells with histamine.

Here we report the isolation of a cDNA encoding the complete human rab18 protein from histamine-stimulated endothelial cells using differential display. The amino acid sequence showed 98% homology with the previously isolated mouse rab18 protein, which is implicated in apical/basolateral endocytosis. Northern blot analysis revealed two transcripts (2.5 kb and 1 kb) ubiquitously expressed in all examined organs, as well as in human umbilical vein endothelial and aortic cells. In blood cells rab18 transcripts were hardly detectable. The histamine-induced time-dependent increase of rab18 mRNA expression in human umbilical vein endothelial cells and peripheral blood mononuclear cells indicates for the first time a link between receptor-mediated signal transduction and the regulation of rab gene expression. This finding might also imply a role for rab proteins in inflammation.

ADP binding induces long-distance structural changes in the beta polypeptide of the chloroplast ATP synthase.

Binding of ADP to the beta polypeptide isolated from the catalytic F1 portion (CF1) of the chloroplast ATP synthase caused an increase of 10-20% in the steady state fluorescence intensity of fluorescent maleimides attached to the cysteine residue at position 63. Fluorescence lifetime distributions indicated that the beta polypeptide switched between two conformational states depending on the presence or absence of bound ADP. The fluorescence enhancement induced by ADP binding allowed a direct calculation of the dissociation constant for ADP of 0.7 microM. ATP did not cause a fluorescence enhancement but competed with ADP for binding to the same site. An apparent dissociation constant of 2 microM was obtained for ATP binding. Fluorescence resonance energy transfer experiments indicated that Cys63 is 42 A away from the nucleotide binding site on the beta polypeptide, confirming a previous measurement [(Colvert, K.K., Mills, D.A., Richter, M.L. (1992) Biochemistry 31, 3930-3935]. Frequency domain fluorescence anisotropy measurements indicated that the beta polypeptide has an irregular, elongated shape which is in good agreement with the conformation found in the crystal structure of the beef heart mitochondrial F1 enzyme [Abrahams, J.P., Leslie, A.G.W., Lutter, R., & Walker, J.E. (1994) Nature 370, 621-628]. The rotational correlation time did not change significantly upon ADP binding, indicating that ADP did not induce a large change in the overall shape of the beta polypeptide. The results show that the nucleotide binding domain and the N-terminal domain of the beta polypeptide communicate with each other over a significant distance via conformational changes.(ABSTRACT TRUNCATED AT 250 WORDS)