A renin-angiotenzin rendszer szerepe a csontátépülés szabályozásában = The role of the renin-angiotensin system in the regulation of bone-remodelling

Számos humorális faktor veszt részt a csontszöveti remodelling szabályozásában. Feltételeztük, hogy a szöveti renin-angiotenzin rendszer (RAS) és a transforming growth factor (TGF)-beta is hatással van az osteoblastok funkciójára. In vitro vizsgáltuk MC3T3-E1 osteoblastok proliferációját és differenciálódását TGF-beta vagy angiotenzin II (Ang II) kezelés hatására. Eredményeink szerint a TGF-beta fokozza az immediate-early gén c-fos expresszióját és az osteoblastok proliferációját, ezzel szemben az gátolja az osteogen differenciációt. Továbbá az Ang II gátolja a proliferációt, de nem befolyásolja az osteogen markerek expresszióját. Az osteogen remodelling befolyásolása az endogén RAS aktivitáson és TGF-beta szintézisen keresztül ígéretes terápiás lehetőségeket kínál. További kutatásokat igényel a fenti jelenségek mögött húzódó intracelluláris események feltárása. | Several humoral factors are known to play role in the regulation of bone remodelling. It is conceivable that local renin-angiotensin system (RAS) and transforming growth factor (TGF)-beta have an impact on osteoblast function. We analysed proliferation and differentiation of MC3T3-E1 osteoblast treated with TGF-beta or angiotensin II (Ang II) in vitro. Our results show that TGF-beta increased the expression of c-fos an immediate early gene and subsequently the proliferation of osteoblasts. On the contrary TGF-beta inhibited the osteogenic differentiation. Moreover angiotensin II inhibited osteoblast proliferation and did not influence differentiation. Regulation of osteogenic remodelling via controlling endogenic RAS activity and TGF-beta synthesis would be an intriguing new therapeutic opportunity. Further investigation is required to clarify the intracellular event leading to these phenomena

Therapeutic Targeting of Fibrotic Epithelial-Mesenchymal Transition–An Outstanding Challenge

Back in 1995, a landmark paper was published, which shaped the fibrosis literature for many years to come. During the characterization of a fibroblast-specific marker (FSP1) in the kidneys, an observation was made, which gave rise to the hypothesis that “fibroblasts in some cases arise from the local conversion of epithelium.” In the following years, epithelial-mesenchymal transition was in the spotlight of fibrosis research, especially in the kidney. However, the hypothesis came under scrutiny following some discouraging findings from lineage tracing experiments and clinical observations. In this review, we provide a timely overview of the current position of the epithelial-mesenchymal transition hypothesis in the context of fibrosis (with a certain focus on renal fibrosis) and highlight some of the potential hurdles and pitfalls preventing therapeutic breakthroughs targeting fibrotic epithelial-mesenchymal transition

Sejt-sejt és sejt-mátrix interakciók szerepe a progresszív vesefibrózis patomechanizmusában = The role of cell-cell and cell-matrix interactions in the pathomechanism of progressive renal fibrosis

A transforming growth factor-beta (TGF) által indukált epithelialis-mesenchymalis transzformáció (EMT) szabályozásában az ERK, a p38-beta MAP kináz, a Smad2 és a Smad3 fehérje is részt vesz. A TGF konfluens sejtrétegben nem idézett elő EMT-t, a sejtkapcsolatok szétkapcsolása visszaállította a TGF EMT-t indukáló hatását. A TGF hatására bekövetkező simaizomsejt aktin (SMA) fehérje termelődés beta-catenin dependens. Modellünk szerint az EMT kialakulásához epithel sérülés és TGF hatás együttesen szükséges. Az adherens junctiok szétkapcsolása aktiválta a p21 Rho GTP-ázt, a Rho kinázt (ROK) és ezen keresztül a myosin könnyű lánc (MLC) kinázt. A sejtkapcsolatok dezintegrációja és a SMA transzkripció közötti kapcsolatban szerepe van a serum response factor (SRF) és a myocardin-related transcription factor (MRTF) Rho dependens nukleáris transzlokációjának. A RhoA mellett a p21 Rac1 és a CDC42 is hozzájárulnak az EMT kiváltásához, míg a p21 Ras GTP-áz gátolta azt. Tubulus sejtekben az angiotenzin II tirozin kinázok közreműködésével fokozta a Plasminogen Activator Inhibitor-1 promóter aktivitását. A proximális renin promóter e sejtekben angiotenzin II hatására paradox módon aktiválódik, s e hatásban a tirozin kinázok mellett a c-Jun-N-terminal Kinase is részt vesz. Végül igazoltuk, hogy a tubulus sejtekben az I. típusú discoidin domain receptor expresszálódik, s e receptort az I. típusú kollagén aktiválja. | ERK, p38-beta MAP kinase, Smad2 and Smad3 proteins contribute to the epithelial-mesenchymal transformation (EMT) induced by transforming growth factor-beta (TGF) in renal tubular cells. TGF did not induce EMT in confluent cultures but TGF readily transformed tubular cells after disruption of cell contacts. Smooth muscle cell actin (SMA) expression was beta-catenin dependent. We suggest a ?two hit? model where both epithelial injury and TGF effect are necessary to induce EMT. Disruption of adherent junctions activated p21 Rho GTP-ase, Rho kinase (ROK) and myosin light chain (MLC) phosphorylation. Rho dependent nuclear translocation of serum response factor (SRF) and myocardin-related transcription factor (MRTF) contributed to SMA transcription induced by disruption of cell contacts. In addition to Rho A both p21 Rac and CDC42 contribute to induction of EMT whereas p21 Ras GTP-ase inhibited this process. Angiotensin II stimulated the activity of the Plasminogen Activator Inhibitor-1 promoter through tyrosine kinases in tubular cells. Interestingly, angiotensin II induced a paradoxical activation of the proximal renin promoter in these cells. Both tyrosine kinases and the c-Jun-N-terminal Kinase contributed to this effect. Finally, we have demonstrated the expression of type I discoidin domain receptor in proximal tubular cells. We have shown that tyrosine phosphorylation of these receptors is induced by fibrillary type I collagen

Post-Ischemic Renal Fibrosis Progression Is Halted by Delayed Contralateral Nephrectomy : The Involvement of Macrophage Activation

(1) Background: Successful treatment of acute kidney injury (AKI)-induced chronic kidney disease (CKD) is unresolved. We aimed to characterize the time-course of changes after contralateral nephrectomy (Nx) in a model of unilateral ischemic AKI-induced CKD with good translational utility. (2) Methods: Severe (30 min) left renal ischemia-reperfusion injury (IRI) or sham operation (S) was performed in male Naval Medical Research Institute (NMRI) mice followed by Nx or S one week later. Expression of proinflammatory, oxidative stress, injury and fibrotic markers was evaluated by RT-qPCR. (3) Results: Upon Nx, the injured kidney hardly functioned for three days, but it gradually regained function until day 14 to 21, as demonstrated by the plasma urea. Functional recovery led to a drastic reduction in inflammatory infiltration by macrophages and by decreases in macrophage chemoattractant protein-1 (MCP-1) and tumor necrosis factor-alpha (TNF-α) mRNA and most injury markers. However, without Nx, a marked upregulation of proinflammatory (TNF-α, IL-6, MCP-1 and complement-3 (C3)); oxidative stress (nuclear factor erythroid 2-related factor 2, NRF2) and fibrosis (collagen-1a1 (Col1a1) and fibronectin-1 (FN1)) genes perpetuated, and the injured kidney became completely fibrotic. Contralateral Nx delayed the development of renal failure up to 20 weeks. (4) Conclusion: Our results suggest that macrophage activation is involved in postischemic renal fibrosis, and it is drastically suppressed by contralateral nephrectomy ameliorating progression

Renal cell carcinoma in end-stage renal disease: A retrospective study in patients from Hungary

Introduction: End-stage renal disease (ESRD) and acquired cystic kidney disease (ACKD) are known risk factors for renal cell carcinoma (RCC). Hereby, the clinicopathological features of RCCs developed in ESRD were investigated. Methods: A database consisting of 34 tumors from 31 patients with ESRD among 2 566 nephrectomy samples of RCC was built. The demographic, clinical, and follow-up data along with pathological parameters were analyzed. The RCCs were diagnosed according to the current WHO Classification of Urinary and Male Genital Tumors. Results: Twenty-two tumors developed in men and 12 in women, with a median age of 56 years (range: 27-75 years). The causes of ESRD were glomerulonephritis (n=7), hypertensive kidney disease (n=6), autosomal dominant polycystic kidney disease (n=6), chronic pyelonephritis (n=4), diabetic nephropathy (n=3), chemotherapy-induced nephropathy (n=1), and undetermined (n=4). ACKD complicated ESRD in 12 patients. The following histological subtypes were identified: clear cell RCC (n=19), papillary RCC (n=5), clear cell papillary tumor (n=5), ACKD RCC (n=3), and eosinophilic solid and cystic RCC (n=2). The median tumor size was 31 mm (range: 10-80 mm), and 32 tumors were confined to the kidney (pT1-pT2). There was no tumor-specific death during the period of this study. Progression was registered in one patient.Conclusion: In our cohort, the most common RCC subtype was clear cell RCC (55%), with a frequency that exceeded international data appreciably (14-25%). The incidence of clear cell papillary tumor and ACKD RCC (14.7% and 8.5%) was lower than data reported in the literature (30% and 40%). Our results indicate a favorable prognosis of RCC in ESRD

Examination of the Effects of Domestic Water Buffalo (Bubalus bubalis) Grazing on Wetland and Dry Grassland Habitats

In nature conservation today, there is a global problem with the aggressive expansion of invasive plant species and the conservation of valuable grassland vegetation. Based on this, the following question has been formed: Is the domestic water buffalo (Bubalus bubalis) appropriate for managing various habitat types? How does grazing by water buffalo (Bubalus bubalis) affect on grassland vegetation? This study was carried out in four areas of Hungary. One of the sample areas was in the Mátra Mountains, on dry grassland areas where grazing had been applied for two, four and six years. The other sample areas were in the Zámolyi Basin, where wet fens with a high risk of Solidago gigantea and in a typic Pannonian dry grassland were investigated. In all areas, grazing was carried out with domestic water buffalo (Bubalus bubalis). During the study, we carried out a coenological survey, examining the change of cover of plant species, their feed values and the biomass of the grassland. According to the results, both the number and cover of economically important grasses (from 28% to 34.6%) and legumes (from 3.4% to 25.4%) increased in Mátra as well as the high proportion of shrubs (from 41.8% to 4.4%) shifted toward grassland species. In the areas of the Zámolyi Basin, invasive Solidago has been suppressed completely, the pasture has been converted completely (from 16% to 1%) and the dominant species has become Sesleria uliginosa. Thus, we have found that grazing with buffalo is suitable as a habitat management method in both dry grasslands and wet grasslands. Therefore, in addition to its effectiveness in the control of Solidago gigantea, grazing with buffalo is successful in both nature conservation and economic aspects of grassland vegetation