Y-box protein-1 is the crucial mediator of antifibrotic interferon-gamma effects.

Y-box protein-1 (YB-1) is a known negative regulator of collagen (Col) expression by two different mechanisms, acting directly through binding to an interferon-gamma response element within the col1A2 promoter and/or by physically interacting with p300/Smad3, thereby abrogating the stimulatory effect of transforming growth factor-beta (TGF-beta). Here, we report that YB-1 activation via the Jak1 signaling pathway is required and sufficient to confer interferon-gamma-dependent activation of the smad7 gene. By binding to a bona fide recognition site within the smad7 promoter, YB-1 up-regulates smad7 transcription, which was additively enhanced by autoinhibitory TGF-beta signaling.

Combined expression of A1 and A20 achieves optimal protection of renal proximal tubular epithelial cells.

Background: Apoptotic death of renal proximal tubular epithelial cells (RPTECs) is a feature of acute and chronic renal failure. RPTECs are directly damaged by ischemia, inflammatory, and cytotoxic mediators but also contribute to their own demise by up-regulating proinflammatory nuclear factor-kappaB (NF-kappaB)-dependent proteins. In endothelial cells, the Bcl family member A1 and the zinc finger protein A20 have redundant and dual antiapoptotic and anti-inflammatory effects.

Expression patterns of PDGF-A, -B, -C and -D and the PDGF-receptors alpha and beta in activated rat hepatic stellate cells (HSC).

The platelet-derived growth factor (PDGF) family, which regulates many physiological and pathophysiological processes has recently been enlarged by two new members, the isoforms PDGF-C and -D. Little is known about the expression levels of these new members in hepatic fibrosis. We therefore investigated by quantitative real time PCR (Taqman) the mRNA expression profiles of all four PDGF isoforms in transdifferentiating primary cultured hepatic stellate cells (HSC), an in vitro model system of hepatic fibrogenesis, either with or without stimulation of the cells with PDGF-BB or TGF-beta1.

Lumbar bone mineral density in very long-term renal transplant recipients: impact of circulating sex hormones.

The influence of circulating sex hormones and gender on the bone mineral density (BMD) in long-term renal transplant recipients needs further investigation. We performed a retrospective analysis of lumbar BMD between 6 years and 20 years after renal transplantation. In 67 patients (47+/-12 years, 38 male) with a minimum interval of 72 months after transplantation, lumbar BMD measurements (dual energy X-ray absorptiometry) were performed (=complete cohort).

Urine protein patterns can serve as diagnostic tools in patients with IgA nephropathy.

Background: IgA nephropathy (IgAN) is the most common chronic glomerular disease in adults. End-stage renal disease (ESRD) develops in about 30% of the patients. Early intervention and consequent therapy may prevent or at least delay the development of ESRD in these patients.

Therapeutic targets for prevention and regression of progressive fibrosing renal diseases.

Renal fibrosis complicates most chronic renal diseases, leading to a progressive loss of function and ultimately resulting in terminal renal failure. Molecular mechanisms underlying the development and progression of renal fibrosis have been increasingly identified, and much progress has been made towards a better understanding of the roles of different growth factors/cytokines and regulators of matrix turnover, as well as of the interactions between renal inflammation and fibrosis. This review focuses on recent advances in the identification of novel targets, as well as the development of new therapeutic tools for use in the treatment of progressive fibrosing renal diseases.

An efficient system for tissue-specific overexpression of transgenes in podocytes in vivo.

The utility of promoter fragments isolated from the 5'-flanking region of endogenous mammalian genes to drive transgene expression in vivo is often limited by low expression levels. In this study, a bigenic system was established that allows constitutive overexpression of transgenes in a tissue-specific fashion in transgenic mice in a time- and cost-effective fashion. A modified floxed expression vector was constructed [CMVflox-enhanced green fluorescent protein (eGFP)], in which a lacZ cassette (beta-galactosidase) flanked by lox sites was placed between a CMV-promoter and the transgene of interest (eGFP).

R-roscovitine (CYC202) alleviates renal cell proliferation in nephritis without aggravating podocyte injury.

Background: Cyclin-dependent kinase (CDK) inhibition is a new therapeutic approach to proliferative glomerulonephritides. CDK2 is required for G(1)/S transition and DNA synthesis and is inhibited by CYC202 (R-roscovitine). Since podocytes express CDK2 in nephritis and since loss of podocytes contributes to glomerulosclerosis, the rationale of the present study was to test whether CDK2 inhibition is safe in instances of podocyte injury.

The chemokine receptor 5 Delta32 mutation is associated with increased renal survival in patients with IgA nephropathy.

Background: Chemokine receptor 5 (CCR5) plays an important role in the recruitment of monocytes and T cells in inflammation and experimental studies suggest that CCR5 might be involved in the pathogenesis of IgA nephropathy. A mutation in the CCR5 gene (CCR5 Delta32), leading to a nonfunctional receptor, was recently described. We therefore evaluated the potential role of this mutation on renal survival in patients with IgA nephropathy.

Heat shock protein 60 is released in immune-mediated glomerulonephritis and aggravates disease: in vivo evidence for an immunologic danger signal.

Heat shock proteins (Hsp) are ubiquitous intracellular proteins that can be released in various forms of cellular stress. Some Hsp, such as Hsp60, have been shown to stimulate directly T cell-mediated immune responses in vitro. Here, it is demonstrated that Hsp60 is released from the kidneys and excreted into the urine of mice with nephrotoxic nephritis (NTN), a model of rapidly progressive glomerulonephritis.

"Missing" inhibitors of calcification: general aspects and implications in renal failure.

In the recent past, it has become increasingly clear that extracellular calcium and phosphate homeostasis is a tightly regulated process. Since the physiological serum concentrations of calcium and phosphate are several orders of magnitude above their solubility product, mechanisms inhibiting precipitation must be operative to prevent extraosseous calcification. A number of local and systemic calcification inhibitors, including fetuin-A, matrix Gla protein, and osteoprotegerin, have been identified in recent years.

Inducible nitric oxide synthase-derived nitric oxide promotes glomerular angiogenesis via upregulation of vascular endothelial growth factor receptors.

The vascular endothelial growth factor (VEGF) system is of major importance for glomerular endothelial repair in glomerulonephritis (GN) and is significantly affected by nitric oxide (NO) release. For investigating whether glomerular upregulation of inducible NO synthase (iNOS) in GN might affect VEGF-mediated repair, a selective iNOS inhibitor, L-N6-(1-iminoethyl)-lysin (L-NIL), was administered to rats with anti-Thy 1.1 GN from day -2 until day 5 after GN induction.

Vascular calcification in patients with end-stage renal disease.

Vascular calcification is the most common type of extra-osseous calcification in end-stage renal disease (ESRD), manifesting as both medial and intimal calcification of large arteries. It is highly prevalent, often progressive and is associated with reduced arterial elasticity and increased mortality. Risk factors for calcification in ESRD include age, duration of dialysis, diabetes mellitus, most probably an elevated calcium-phosphorus product (Ca x P) level, the dose of calcium-containing phosphate binders and the induction of the systemic inflammatory response.

Mesangial cell expression of proto-oncogene Ets-1 during progression of mesangioproliferative glomerulonephritis.

Background: Ets-1 is a transactivator of matrix-associated genes and key factor in neoangiogenesis. The expression of Ets-1 mRNA and protein was analyzed in healthy rat kidney and in a model for mesangioproliferative disease without and with inhibition of platelet-derived growth factor-B (PDGF-B) activity.

Methods: Immunohistochemistry was performed using a specific noncrossreacting anti-Ets-1 antibody and included a counterstain with alpha-smooth muscle actin (alpha-SMA).

Recurrent IgA nephropathy after renal transplantation.

Recurrence of the original disease is now the third most frequent cause of allograft loss at 10 years after transplantation in patients with underlying glomerulonephritis. IgA nephropathy (IgAN), the most common type of glomerulonephritis, histologically recurs in up to 60% of the patients. Initially considered to be a relatively benign phenomenon, several studies, which included a total of almost 1200 patients with underlying IgAN, have now established that after a mean follow up of 5 years, approximately 13% of the patients will exhibit some recurrence-related renal graft dysfunction and approximately 5% will have lost their graft as a result of recurrent IgAN.

Biocompatibility of peritoneal dialysis fluids: long-term exposure of nonuremic rats.

Objectives: Long-term peritoneal dialysis (PD) leads to structural and functional changes in the peritoneum. The aim of the present study was to investigate the long-term effects of PD fluid components, glucose and glucose degradation products (GDP), and lactate-buffered solution on morphology and transport characteristics in a nonuremic rat model.

Methods: Rats were subjected to two daily intraperitoneal injections (20 mL/day) during 12 weeks of one of the following: commercial PD fluid (Gambrosol, 4%; Gambro AB, Lund, Sweden), commercial PD fluid with low GDP levels (Gambrosol trio, 4%; Gambro AB), sterile-filtered PD fluid (4%) without GDP, or a glucose-free lactate-buffered PD fluid.

Factor Xa-activated whole blood clotting time (Xa-ACT) for bedside monitoring of dalteparin anticoagulation during haemodialysis.

Background: Low molecular weight heparins (LMWH) like dalteparin are increasingly used for anticoagulation during haemodialysis (HD). The available laboratory tests for monitoring LMWH anticoagulation are time-consuming and expensive, and the suitability of the conventional activated clotting time (ACT) is controversial. A simple and cheap bedside test would be useful.

Identification and functional characterization of dendritic cells in the healthy murine kidney and in experimental glomerulonephritis.

The kidney tubulointerstitium contains numerous bone marrow-derived antigen-presenting cells, which are often referred to as resident tissue macrophages, although several previous studies had demonstrated characteristics of dendritic cells (DC). In this study, we describe a subset of tubulointerstitial cells expressing the DC marker CD11c. A protocol was established to isolate these cells for in vitro analysis.

No association of the -2518 MCP-1 A/G promoter polymorphism with incidence and clinical course of IgA nephropathy.

Background: The clinical course of IgA nephropathy is highly variable, ranging from complete remission to progression with end-stage renal disease. Although the mechanisms involved in disease progression are not characterized in detail, loss of renal function is positively correlated with mononuclear cell infiltration. In general, chemokines play an important role in the directional recruitment of inflammatory cells.

A fully human monoclonal antibody (CR002) identifies PDGF-D as a novel mediator of mesangioproliferative glomerulonephritis.

PDGF-B is of central importance in mesangioproliferative diseases. PDGF-D, a new PDGF isoform, like PDGF-B, signals through the PDGF betabeta-receptor. The present study first determined that PDGF-D is mitogenic for rat mesangial cells and is not inhibited by a PDGF-B antagonist.