Albumin up-regulates the type II transforming growth factor-beta receptor in cultured proximal tubular cells1

Albumin up-regulates the type II transforming growth factor-beta receptor in cultured proximal tubular cells.BackgroundClinical and experimental observations suggest that proteinuria is not merely a marker of chronic nephropathies, but may also be involved in the progression to end-stage renal failure. Filtered proteins are taken up by tubular cells, and overwhelming this system may lead to tubular synthesis of various proinflammatory and profibrogenic cytokines, including transforming growth factor-beta (TGF-β). TGF-β acts by first binding to specific receptors. We studied in an in vitro system using a well-defined mouse proximal tubular cell line (MCT cells) whether fatty acid-free bovine albumin modulates expression of specific receptors for TGF-β.MethodsMCT (and LLC-PK1) cells were challenged in serum-free medium with different concentrations of albumin. Activation of a local renin-angiotensin system was tested by real-time polymerase chain reaction (PCR) for renin and angiotensinogen transcripts and determination of secreted angiotensin II (Ang II) by enzyme-linked immunosorbent assay (ELISA). Some cells were also treated with the AT1 receptor antagonist losartan. TGF-β receptor types I and II mRNA levels were determined by Northern analysis whereas protein abundance was measured by Western blots. To test for a functional consequence of up-regulated TGF-β receptors, MCT cells were preincubated with albumin and subsequently treated with low-dose TGF-β that normally does not induce collagen type IV expression by itself. Downstream signaling events were detected by Western blots for phosphorylated Smad2. Scatchard assays with [125I]TGF-β1 were performed to estimate affinity and number of specific binding sites. Different length TGF-β type II promoter constructs linked to CAT reporter were transiently transected into MCT cells to determine transcriptional activity.ResultsIncubation of MCT cells with 0.5 to 10 mg/mL albumin leads to an increase in type II TGF-β receptor mRNA and protein expression without influencing type I receptors. An increase in type II TGF-β receptor protein expression was detected after 12 hours of albumin incubation and was still detectable after 48 hours. The albumin-mediated increase in type II TGF-β receptor mRNA was attenuated in the presence of 1 μmol/L losartan, suggesting involvement of a local renin-angiotensin system. MCT cells treated with albumin significantly increased expression of angiotensinogen and renin transcripts and also secreted more Ang II into the culture supernatant. Analysis of transcriptional activity showed that promoter segments containing activating protein (AP-1)-binding sites are necessary for albumin-induced transcription of the TGF-β type II receptor. Binding assays revealed that albumin treatment significantly increased the overall binding sites as well as the affinity for TGF-β. This effect had functional consequences because MCT cells pretreated with albumin reacted with a stronger TGF-β–mediated phosphorylation of down-stream Smad2 and also increased collagen IV expression compared with control cells.ConclusionOur findings indicate that albumin up-regulates ligand-binding TGF-β receptors on cultured proximal tubular cells. Albumin-induced activation of local Ang II production appears to be responsible for this effect. This may amplify the matrix-stimulatory actions of TGF-β on tubular cells and could be a novel mechanism for how proteinuria exhibits pathophysiologic effects on tubular cells ultimately leading to tubulointerstitial fibrosis

Immune-mediated mesangial cell injury—Biosynthesis and function of prostanoids

Immune-mediated mesangial cell injury—Biosynthesis and function of prostanoids. We studied the formation of cyclo-oxygenase products in a rat model of mesangial cell injury, in order to determine a possible role of prostaglandin E2 (PGE2), prostaglandin I2 (determined as 6-keto-PGF1α and thromboxane A2 (TxA2) in immune-mediated glomerular disease. Selective immune-mediated mesangial cell injury was induced by i.v. administration of a rabbit anti-rat thymocyte antiserum (ATS). Intravenous ATS leads to immune deposits in the mesangium followed by mesangiolysis and the infiltration of polymorphonuclear granulocytes and monocytes. Glomerular TxB2 formation two hours (292 ± 27 pg/mg/min) and 48 hours (396 ± 69 pg/mg/min) following antibody was significantly (P < 0.05) higher compared to animals receiving non-antibody rabbit IgG (TxB2: 2hr 143 ± 13; 48hr 171 ± 32 pg/mg/min). Treatment with cobra venom factor (CVF) and the reduction of glomerular monocyte infiltration inhibited the increase of glomerular TxB2 formation significantly. Depletion of granulocytes with a rabbit anti-rat granulocyte serum had no effect on glomerular prostanoid formation following ATS. Glomerular PGE2 and 6-keto PGF1α production was not altered following ATS. Inulin clearance in rats with immune-mediated mesangial cell injury was significantly (P < 0.001) lower at two hours (456 ± 24 µl/min/100g body wt) and 48 hours (433 ± 54 µl/min/lOO g body wt) compared to their corresponding control animals which were treated with non-antibody IgG (2 hr: 914 ± 51; 48 hr: 694 ± 79 µl/min/100g body wt). Pretreatment of rats with indomethacin (Indo) or with the thromboxane synthetase inhibitor UK 38485 prevented the decrease in inulin clearance following ATS at two hours (Indo: 800 ± 67; UK 38485: 923 ± 115) and at 48 hours (Indo: 697 ± 60; UK 38485: 654 ± 99). The data demonstrate that selective, immune-mediated mesangial cell injury in rats is associated with increased glomerular TxB2 formation. Complement and monocyte/macrophage depletion reduces TxB2 production. The fall in inulin clearance following ATS is ameliorated when the rats receive indomethacin or the Tx synthetase inhibitor UK 38485. Thus, elevated TxB2 formation might mediate the reduction in GFR in this model of glomerular immune injury

Wiederholungsbefragungen - ein unmögliches Unterfangen in Zeiten des Datenschutzes? Bericht über die Vorgehensweise bei einer arbeitssoziologischen Längsschnittuntersuchung

Die Autoren beschreiben die Problemfelder und deren mögliche Lösungswege, in mehrjährigem Abstand den Kontakt zu den Befragten in Längsschnittuntersuchungen aufrechtzuerhalten. Die konkreten Erfahrungen resultieren aus einem Projekt, das die Gültigkeit der Sozialisations- und Generalisierungshypothese versus der Selektions- und Fithypothese in der beruflichen Sozialisation Erwachsener prüft. Für die Wiederholungsbefragung waren verschiedene Vorkehrungen getroffen worden, wie Auswahl der Probanden innerhalb einer großen Arbeitsorganisation, hier die Bediensteten der Verwaltung einer westdeutschen Großstadt und der nach der Privatanschrift der Befragten, die, unabhängig von den bereits ausgefüllten Fragebogen der ersten Welle verwahrt, beim Feldzugang zur zweiten Welle benutzt werden konnte. Darüber hinaus wurde in Fällen, in denen die Postanschrift nicht mehr aktuell war bzw. die aus der ehemaligen Arbeitsstelle ausgeschieden waren, eine Verbleibsforschung angestellt, bei der die herangezogenen Informationsquellen sehr gut zur Ermittlung der Befragten beitrugen. Die Erhebungsphase verzögerte sich dadurch jedoch im Vergleich zur ersten Befragung. (HN

THSD7A Positivity Is Associated with High Expression of FAK in Prostate Cancer

Prostate cancer is one of the most common malignancies, and there are a wide range of treatment options after diagnosis. Most prostate cancers behave in an indolent manner. However, a given sub-group has been shown to exhibit aggressive behavior; therefore, it is desirable to find novel prognostic and predictive (molecular) markers. THSD7A expression is significantly associated with unfavorable prognostic parameters in prostate cancer. FAK is overexpressed in several tumor types and is believed to play a role in tumor progression and metastasis. Furthermore, there is evidence that THSD7A might affect FAK-dependent signaling pathways. To examine whether THSD7A expression has an impact on the expression level of FAK in its unphosphorylated form, a total of 461 prostate cancers were analyzed by immunohistochemistry using tissue microarrays. THSD7A positivity and low FAK expression were associated with adverse pathological features. THSD7A positivity was significantly associated with high FAK expression. To our knowledge we are the first to show that THSD7A positivity is associated with high FAK expression in prostate cancer. This might be proof of the actual involvement of THSD7A in FAK-dependent signaling pathways. This is of special importance because THSD7A might also serve as a putative therapeutic target in cancer therapy

THSD7A Positivity Predicts Poor Survival and Is Linked to High FAK Expression and FGFR1-Wildtype in Female Patients with Squamous Cell Carcinoma of the Lung

Lung cancer is the leading cause of cancer-related deaths in the western world, with squamous cell carcinoma being one of the most common histological subtypes. Prognostic and predictive markers are still largely missing for squamous cell carcinoma of the lung (LSCC). Several studies indicate that THSD7A might at least play a role in the prognosis of different tumors. FAK seems to play an important role in lung cancer and is discussed as a potential therapeutic target. In addition, there is evidence that FAK-dependent signaling pathways might be affected by THSD7A. For that reason, we investigated the role of THSD7A as a potential tumor marker in LSCC and whether THSD7A expression has an impact on the expression level of FAK. A total of 101 LSCCs were analyzed by immunohistochemistry using tissue microarrays. THSD7A positivity was associated with poor overall survival in female patients and showed a relation to high FAK expression in this subgroup. To our knowledge, we are the first to report these correlations in lung cancer. The results might be proof of the assumed activation of FAK-dependent signaling pathways by THSD7A and that as a membrane-associated protein, THSD7A might serve as a putative therapeutic target in LSCC

SCARA5 Is Overexpressed in Prostate Cancer and Linked to Poor Prognosis

Prostate cancer is one of the most common malignancies worldwide, showing a wide range of clinical behaviors. Therefore, several treatment options arise out of the diagnosis “prostate cancer”. For this reason, it is desirable to find novel prognostic and predictive markers. In former studies, we showed that THSD7A expression is associated with unfavorable prognostic parameters in prostate cancer and is linked to a high expression of focal adhesion kinase (FAK). Recently, scavenger receptor class A member 5 (SCARA5) was reported to be the downstream gene of THSD7A in esophageal squamous cell carcinoma. SCARA5 is believed to play an important role in the development and progression of several different tumor types. Most studies describe SCARA5 as a tumor suppressor. There is also evidence that SCARA 5 interacts with FAK. To examine the role of SCARA5 as a potential biomarker in prostate cancer, a total of 461 prostate cancers were analyzed via immunohistochemistry using tissue microarrays. Furthermore, we compared the expression level of SCARA5 with our previously collected data on THSD7A and FAK. High SCARA5 expression was associated with advanced tumor stage (p < 0.001), positive nodal status (p < 0.001) and high Gleason-score (p < 0.001). At least, strongly SCARA5-positive cancers were associated with THSD7A-positivity. There was no significant association between SCARA5 expression level and FAK expression level. To our knowledge, we are the first to investigate the role of SCARA5 in prostate cancer and we demonstrated that SCARA5 might be a potential biomarker in prostate cancer

The Diversity Factor: How Cultural Diversity Impacts Innovations in Germany

The 2018 Reinhard Mohn Prize on “Living Diversity – Shaping Society” is meant to bring new momentum and perspectives to how Germany lives diversity and shapes society. The present study “The Diversity Factor – How Cultural Diversity Impacts Innovations in Germany” examines the question of whether and how cultural diversity affects the innovative power of both companies and society. There is much to suggest that a culturally diverse workforce – e.g. people with different experiences, mindsets and interpretive contexts – fosters creativity and innovation. The current publication is based on evaluations of empirical studies that examine the correlation between cultural diversity and innovation. This analysis of the literature was carried out using a narrow definition of cultural diversity, one that includes, in particular, the dimensions of “ethnicity,” “religion/world view” and “nationality.” Innovation was measured in each study based on the number of patents, patent citations or companies’ self-assessments of their product and process innovations or overall factor productivity. The results of this research were then considered more deeply in interviews and conversations with business experts, public administrators and civil society leaders

Glomerular expression of p27Kip1 in diabetic db/db mouse: Role of hyperglycemia

Glomerular expression of p27Kip1 in diabetic db/db mouse: Role of hyperglycemia Early diabetic nephropathy is characterized by glomerular hypertrophy. Previous studies in vitro have demonstrated that mesangial cells exposed to high glucose are arrested in the G1-phase of the cell cycle and express increased levels of the cyclin-dependent kinase inhibitor p27Kip1. The present study was performed to investigate the renal expression of p27Kip1 in db/db mice, a model of diabetes mellitus type II. Glomerular p27Kip1 protein, but not mRNA expression, was strongly enhanced in diabetic db/db mice compared with non-diabetic db/+ littermates. Immunohistochemical studies revealed that this stimulated expression was mainly restricted to the nuclei of mesangial cells and podocytes, but glomerular endothelial cells occasionally also stained positively. Quantification of p27Kip1 positive glomerular cells showed a significant increase of these cells in db/db mice compared with non-diabetic db/+ animals. Although tubular cells revealed a positive staining for p27Kip1 protein, there was no difference between db/+ and db/db mice. Immunoprecipitation experiments revealed that p27Kip1 protein associates with Cdk2 and Cdk4, but not with Cdk6. To test for the influence of hyperglycemia on cell cycle arrest and p27Kip1 expression, mesangial cells were isolated from db/+ and db/db mice. There was a similar basal proliferation when these cells were grown in normal glucose-containing medium (100 mg/dl). However, raising the glucose concentration to 275 to 450 mg/dl induced cell cycle arrest in db/+ as well as db/db mesangial cells. Increasing the medium osmolarity with D-mannitol failed to induce p27Kip1 expression in mesangial cells. Transfection of cells with p27Kip1 antisense, but not missense, phosphorothioate oligonucleotides facilitated cell cycle progression equally well in db/+ and db/db mesangial cells. Furthermore, p27Kip1 expression was comparable in both cell lines in normal glucose, but increased in high glucose medium. Our studies demonstrate that p27Kip1 expression is enhanced in diabetic db/db animals. This induction appears to be due to hyperglycemia. Expression of p27Kip1 may be important in cell cycle arrest and hypertrophy of mesangial cells during early diabetic nephropathy

Chronic anti-Thy-1 nephritis is aggravated in the nonclipped but not in the clipped kidney of Goldblatt hypertensive rats

Chronic anti-Thy-1 nephritis is aggravated in the nonclipped but not in the clipped kidney of Goldblatt hypertensive rats.BackgroundWe have previously shown that renovascular hypertension does not inhibit healing of the acute Thy-1 nephritis. To test whether a chronic model of the Thy-1 nephritis is more susceptible to high blood pressure, the repetitive hit model was evaluated in rats with 2-kidney, 1-clip Goldblatt hypertension.MethodsSix weeks after initiation of 2-kidney, 1-clip hypertension, chronic Thy-1 glomerulonephritis was induced in hypertensive rats by four consecutive injections of rabbit antiserum in weekly intervals. Renal structure and function were examined two weeks after the last injection. Glomerular binding of rabbit IgG as well as expression of transforming growth factor-beta (TGF-β), α-smooth muscle actin (α-SMA) and cyclooxygenase (COX)-1 and -2 were evaluated by Western blotting.ResultsSimilar glomerular deposition of rabbit IgG was detected in normotensive rats and in both kidneys of Goldblatt hypertensive rats indicating similar delivery and binding of the heterologous antibody. Induction of the repetitive Thy-1 model significantly enhanced glomerular damage in the nonclipped kidney and increased albuminuria. Surprisingly, no glomerular damage developed in the clipped kidney of nephritic hypertensive rats. In contrast, increased glomerular volume and increased expression of TGF-β, α-SMA as well as COX-1 and COX-2 were found in normotensive nephritic rats and in both kidneys of nephritic hypertensive rats.ConclusionGlomerular and tubulointerstitial damage of the chronic Thy-1 model is dramatically enhanced in the nonclipped kidneys of Goldblatt hypertensive rats. In contrast, the clipped kidney is completely protected from this immunological injury despite similar activation of glomerular cells, induction of TGF-β, COX-1 and COX-2 and glomerular hypertrophy

Die GESIS im Urteil der Profession: Ergebnisse einer Befragung von Soziologieprofessorinnen und -professoren

Die Autoren berichten über die Ergebnisse einer telefonischen Befragung deutschsprachiger Soziologieprofessorinnen und -professoren in Deutschland, Österreich und der Schweiz, die vom 9. November bis 14. Dezember 2000 durchgeführt wurde. Im Rahmen der Qualitätssicherung der Gesellschaft Sozialwissenschaftlicher Infrastruktureinrichtungen (GESIS) diente die Befragung dazu, die Nutzung und Bewertung der Produkte und Dienstleistungen der GESIS zu erfassen. Die Gruppe der Soziologieprofessorinnen und -professoren wurde ausgewählt, da diese zur Kerngruppe der (potenziellen) Nutzer der GESIS gehören und angenommen wird, dass sie über eine besondere Expertise zur Beurteilung der Produkte und Dienstleistungen der GESIS verfügen. Die Befragungsergebnisse werden hinsichtlich des Bekanntheitsgrades der GESIS sowie der jeweiligen Nutzung und Bewertung des Informationszentrums Sozialwissenschaften (IZ), des Zentralarchivs für Empirische Sozialforschung (ZA) und des Zentrums für Umfragen, Methoden und Analysen (ZUMA) zusammenfassend dargestellt. (ICI