Relative roles of endothelin-1 and angiotensin II in experimental post-ischaemic acute renal failure

Background. The relative roles of endothelin (ET)-1 and angiotensin (ANG) II in post-ischaemic acute renal failure (ARF) have not been fully established so far. With the aim of contributing to this goal, we assessed in this study the effect of ANG II and ET-1 blockade on the course of post-ischaemic-ARF. Methods. Anaesthetized Wistar rats received i.v. either bosentan (a dual ET receptor antagonist; 10 mg/kg body weight) or losartan [ANG II type 1 (AT(1)) receptor antagonist; 5 or 10 mg/kg body weight] or both, 20 min before, during and 20 min after ischaemia. Rats in the control group received the vehicle via the same route. Survival and renal function were monitored up to 8 days after the ischaemic challenge, while haemodynamic parameters were measured 24 h after ARF. Results. Our results demonstrate that bosentan treatment has a more beneficial effect on experimental ARF than losartan. The survival rate was remarkably higher in bosentan-treated rats than in both rat groups treated with losartan. In the ARF group treated with bosentan, renal blood flow (RBF) was increased by 129% in comparison with the untreated ARF group, whereas in the losartan-treated ARF groups, RBF was only similar to35 or 38% higher than in control ARF rats. The glomerular filtration rate was markedly higher in bosentan-treated rats than in all other ARF groups on the first and second day after ischaemia. Tubular cell injury was less severe in bosentan-treated rats than in the control ARF rats, but in losartan-treated groups it was similar to that in the ARF group. Concurrent blockade of both ET and AT(1) receptors did not improve ARF because this treatment induced a marked decrease in blood pressure. Conclusions. These results suggest that ET-1 blockade is more efficient in improving the early course of post-ischaemic renal injury than ANG II inhibition, and that blockade of ET-1 might be effective in prophylaxis of ischaemic ARF

Endotel-zavisna relaksacija unutrašnje torakalne arterije prouzrokovana rezveratrolom

Resveratrol, a polyphenol present in wine, has been thought to be responsible for cardiovascular benefits associated with moderate wine consumption. It is also present in the plant Polygonum Cuspidatum. The mechanism of cardiovascular benefits probably includes vasorelaxation, antioxidant and anti-platelet effects of resveratrol. The mechanisms by which resveratrol causes vasodilatation are uncertain. The aim of this study was to investigate the mechanism(s) of resveratrol induced vasorelaxation in human internal mammary artery (HIMA) with endothelium. HIMA rings were precontracted by phenylephrine. Resveratrol induced relaxation of the HIMA rings with endothelium. LNAME, an inhibitor of NO synthase, and methylene blue, an inhibitor of guanylate cyclase, abolished relaxation of HIMA induced by resveratrol. Highly selective blocker of ATP-sensitive K channels, glibenclamide as well as a nonselective blocker of big Ca-sensitive K+ channels, charybdotoxin did not block resveratrol-induced relaxation of HIMA. 4-Aminopyridine and margatoxin, blockers of voltage-gated K+ (KV) channels, abolished endothelium-dependent relaxation of HIMA, induced by resveratrol. In conclusion, we have shown that resveratrol induces relaxation of HIMA with endothelium. It seems that NO and smooth muscle KV channels are included in this relaxation.Smatra se da rezveratrol kao jedna polifenolna komponenta prisutna u značajnim količinama u crnom vinu, smanjuje rizik od razvoja ateroskleroze i koronarne bolesti. U mehanizam kardioprotektivnog delovanja verovatno su uključ eni antioksidativno, antitrombocitno i vazodilatatorno delovanje rezveratrola. Mehanizam vazodilatacije još uvek nije poznat, pa je cilj ovog rada bio da se ispitaju efekti i mehanizam vazorelaksantnog delovanja rezveratrola na humanoj unutraš njoj torakalnoj arteriji sa endotelom. Unutrašnja torakalna arterija je prekontrahovana fenilefrinom. Rezveratrol je koncentracijski-zavisno relaksirao unutrašnju torakalnu arteriju čoveka. L-NAME, inhibitor NO sintaze, i metilensko plavo, inhibitor solubilne gvanilat ciklaze, su antagonizovali relaksaciju unutrašnje torakalne arterije sa intaktnim endotelom, prouzrokovanu rezveratrolom. Visoko selektivni blokator ATP-senzitivnih K+ kanala, glibenklamid, kao i neselektivni blokator velikih Ca-senzitivnih K+ kanala, karibdotoksin nisu antagonizovali rezveratrolom indukovanu relaksaciju unutrašnje torakalne arterije. 4-Aminopiridin i margatoksin, blokatori voltažnih K+ kanala su antagonizovali relaksaciju prouzrokovanu rezveratrolom. Na osnovu ovih činjenica se može zaključiti da je endotel-zavisna relaksacija unutrašnje torakalne arterije čoveka, prouzrokovana rezveratrolom, verovatno posredovana NO. Izgleda, da su 4-aminopiriin- i margatoksin-senzitivni K-kanali smešteni u membrani vaskularnih glatko-mišićnih ćelija humane unutrašnje torakalne arterije, uključeni u mehanizam endotel-zavisne relaksacije prouzrokovane rezveratrolom

Human Cytomegalovirus Induces TGF-β1 Activation in Renal Tubular Epithelial Cells after Epithelial-to-Mesenchymal Transition

Human cytomegalovirus (HCMV) infection is associated epidemiologically with poor outcome of renal allografts due to mechanisms which remain largely undefined. Transforming growth factor-β1 (TGF-β1), a potent fibrogenic cytokine, is more abundant in rejecting renal allografts that are infected with either HCMV or rat CMV as compared to uninfected, rejecting grafts. TGF-β1 induces renal fibrosis via epithelial-to-mesenchymal transition (EMT) of renal epithelial cells, a process by which epithelial cells acquire mesenchymal characteristics and a migratory phenotype, and secrete molecules associated with extracellular matrix deposition and remodeling. We report that human renal tubular epithelial cells infected in vitro with HCMV and exposed to TGF-β1 underwent morphologic and transcriptional changes of EMT, similar to uninfected cells. HCMV infected cells after EMT also activated extracellular latent TGF-β1 via induction of MMP-2. Renal epithelial cells transiently transfected with only the HCMV IE1 or IE2 open reading frames and stimulated to undergo EMT also induced TGF-β1 activation associated with MMP-2 production, suggesting a role for these viral gene products in MMP-2 production. Consistent with the function of these immediate early gene products, the antiviral agents ganciclovir and foscarnet did not inhibit TGF-β1 production after EMT by HCMV infected cells. These results indicate that HCMV infected renal tubular epithelial cells can undergo EMT after exposure to TGF-β1, similar to uninfected renal epithelial cells, but that HCMV infection by inducing active TGF-β1 may potentiate renal fibrosis. Our findings provide in vitro evidence for a pathogenic mechanism that could explain the clinical association between HCMV infection, TGF-β1, and adverse renal allograft outcome

Characterization of the macrophage transcriptome in glomerulonephritis-susceptible and -resistant rat strains

Crescentic glomerulonephritis (CRGN) is a major cause of rapidly progressive renal failure for which the underlying genetic basis is unknown. WKY rats show marked susceptibility to CRGN, while Lewis rats are resistant. Glomerular injury and crescent formation are macrophage-dependent and mainly explained by seven quantitative trait loci (Crgn1-7). Here, we used microarray analysis in basal and lipopolysaccharide (LPS)-stimulated macrophages to identify genes that reside on pathways predisposing WKY rats to CRGN. We detected 97 novel positional candidates for the uncharacterised Crgn3-7. We identified 10 additional secondary effector genes with profound differences in expression between the two strains (>5-fold change, <1% False Discovery Rate) for basal and LPS-stimulated macrophages. Moreover, we identified 8 genes with differentially expressed alternatively spliced isoforms, by using an in depth analysis at probe-level that allowed us to discard false positives due to polymorphisms between the two rat strains. Pathway analysis identified several common linked pathways, enriched for differentially expressed genes, which affect macrophage activation. In summary, our results identify distinct macrophage transcriptome profiles between two rat strains that differ in susceptibility to glomerulonephritis, provide novel positional candidates for Crgn3-7, and define groups of genes that play a significant role in differential regulation of macrophage activity

Application optimality of numerical methods for formfinding of the preliminary and deformed geometry of membrane structures

Овај рад се бави оптималношћу метода за генерисање почетнегеометрије претходно затегнутих, тензилних конструкција, анализом и поређењем резултата ових метода, као и софтверских пакетау којем су имплементиране...This work deals with optimality of the existing form.finding methods for generation of initial geometry of tensile structures..

Application optimality of numerical methods for formfinding of the preliminary and deformed geometry of membrane structures

Овај рад се бави оптималношћу метода за генерисање почетнегеометрије претходно затегнутих, тензилних конструкција, анализом и поређењем резултата ових метода, као и софтверских пакетау којем су имплементиране...This work deals with optimality of the existing form.finding methods for generation of initial geometry of tensile structures..

Analytic equivalence of plane curve singularities yn +xαy +xβa(x) = 0

There are not many examples of complete analytical classification of specific families of singularities, even in the case of plane algebraic curves. In 1989, Kang and Kim published a paper on analytical classification of plane curve singularities yn+a(x)y+b(x) = 0, or, equivalently, yn+xαy+xβA(x) = 0 where A(x) is a unit in Ct{x}, α and β are integers, α _ n − 1 and β _ n. The classification was not complete in the most difficult case α n−1 = β n. In the present paper, the classification is extended also in this case, the proofs are improved and some gaps are removed