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Background: A majority of the current debates in experimental animal science research focus to a large extent on the significance and implementation of the 3Rs principle according to Russell and Burch. In this context, not least due to the EU Directive 2010/63/EU, the concept of a culture of care has become more prevalent. Although animals are essential actors in the field of laboratory science, the discussion around animal agency, as well as the resulting consequences for laboratory animal science, is currently unconsidered. Methods: The purpose of this qualitative survey was to identify the perception and understanding of professional workers in laboratory animal science regarding the culture of care in general and aspects of animal agency in particular. Using a non-standardized qualitative survey method (topic-oriented, guideline-based expert interviews), persons involved in animal experimentation in different groups (management, science, regulation, and care) were interviewed. Results: Overall, the results of the qualitative survey showed that animal agency plays a subordinate role in the question of a culture of care in animal research. Although not all groups explicitly applied the construct of animal agency or comparable terminology for this, there were links to the theoretical construct. Overall, the interviews showed a recognized network between humans and animals and that animals can interact dialogically in research. This is justified, for example, by the transfer of emotions from carers or scientists to animals. Nevertheless, a differentiated reflection of an animal's agency remains disregarded. Conclusion: The present qualitative survey approached the understanding of a culture of care among experts in the field of animal research. Animal agency does occur in the theoretical reception of the culture of care model. However, it is not conclusively established in everyday practice. Rather, the results lead to the assumption that strategies are being implemented to largely fade out animal agency. [ABSTRACT FROM AUTHOR]

Simple Summary: Mice can be housed in metabolic cages in order to answer specific scientific questions. The base of this cage system consists of a metal wire mesh in order to collect urine and feces of mice held therein. The food and water intake can also be assessed. The housing of mice in metabolic cages is considered highly stressful and cold stress is also often addressed because these social animals are single-housed and no further materials (e.g., nesting material) are provided to them. Therefore, in this study, we aimed to reduce stress during metabolic cage housing for mice. An innovative metabolic cage was constructed with integrated cage design improvements and was directly compared with a commercially available metabolic cage and a control cage. The following parameters were selected to evaluate the stress of laboratory mice: body weight, body composition, food intake, cage and body surface temperature, messenger ribonucleic acid (mRNA) expression of uncoupling protein 1 (Ucp1) in brown adipose tissue (BAT), fur score, and fecal corticosterone metabolites (CMs). Our results clearly show that metabolic cage housing elicits a stress response in mice, which is related to the cold housing conditions. The innovative metabolic cage represents a first attempt to reduce cold stress during metabolic cage housing. Housing in metabolic cages can induce a pronounced stress response. Metabolic cage systems imply housing mice on metal wire mesh for the collection of urine and feces in addition to monitoring food and water intake. Moreover, mice are single-housed, and no nesting, bedding, or enrichment material is provided, which is often argued to have a not negligible impact on animal welfare due to cold stress. We therefore attempted to reduce stress during metabolic cage housing for mice by comparing an innovative metabolic cage (IMC) with a commercially available metabolic cage from Tecniplast GmbH (TMC) and a control cage. Substantial refinement measures were incorporated into the IMC cage design. In the frame of a multifactorial approach for severity assessment, parameters such as body weight, body composition, food intake, cage and body surface temperature (thermal imaging), mRNA expression of uncoupling protein 1 (Ucp1) in brown adipose tissue (BAT), fur score, and fecal corticosterone metabolites (CMs) were included. Female and male C57BL/6J mice were single-housed for 24 h in either conventional Macrolon cages (control), IMC, or TMC for two sessions. Body weight decreased less in the IMC (females—1st restraint: −6.94%; 2nd restraint: −6.89%; males—1st restraint: −8.08%; 2nd restraint: −5.82%) compared to the TMC (females—1st restraint: −13.2%; 2nd restraint: −15.0%; males—1st restraint: −13.1%; 2nd restraint: −14.9%) and the IMC possessed a higher cage temperature (females—1st restraint: 23.7 °C; 2nd restraint: 23.5 °C; males—1st restraint: 23.3 °C; 2nd restraint: 23.5 °C) compared with the TMC (females—1st restraint: 22.4 °C; 2nd restraint: 22.5 °C; males—1st restraint: 22.6 °C; 2nd restraint: 22.4 °C). The concentration of fecal corticosterone metabolites in the TMC (females—1st restraint: 1376 ng/g dry weight (DW); 2nd restraint: 2098 ng/g DW; males—1st restraint: 1030 ng/g DW; 2nd restraint: 1163 ng/g DW) was higher compared to control cage housing (females—1st restraint: 640 ng/g DW; 2nd restraint: 941 ng/g DW; males—1st restraint: 504 ng/g DW; 2nd restraint: 537 ng/g DW). Our results show the stress potential induced by metabolic cage restraint that is markedly influenced by the lower housing temperature. The IMC represents a first attempt to target cold stress reduction during metabolic cage application thereby producing more animal welfare friendlydata. [ABSTRACT FROM AUTHOR]

Simple Summary: Animals play a crucial role in social occupational fields. The positive effects of animals are described in theory and practice. However, the significance of animal welfare in animal-assisted intervention settings has not yet been extensively researched. In the present project, individual views on animal welfare are analyzed based on interviews with professionals working with animals. As a result, it can be stated that animal welfare plays an important role for those working in animal-assisted interventions. The structure and design of assignments, animal-related aspects, and conditions as well as education and knowledge are mentioned as generally relevant conditions for compliance with animal welfare from the perspective of animal-assisted intervention practitioners. In addition, concrete courses of action to ensure animal welfare are described. These include stopping or changing the setting at different levels. It is not possible to assess the actual implementation of animal-assisted intervention settings in the context of animal welfare. Further studies are needed to analyze this. Background: Animals play a crucial role in social occupational fields. The positive effects of animals are described in theory and practice. However, the significance of animal welfare in animal-assisted intervention settings has not yet been extensively researched, so that the aim of this explorative study was to investigate the perception and significance as well as the understanding of animal welfare and its implementation on the part of professionals working with animals. Methods: In the present project, 270 animal-assisted professionals from Germany were interviewed about their individual perceptions of animal welfare and their implementation of animal welfare with the help of questionnaires with closed questions (5-point agreement scale) and open questions. The quantitative data were analyzed using the statistical software SPSS and MS Excel. The qualitative data were analyzed using thematic coding. Results: The quantitative and qualitative results show that animal welfare poses high importance for people working in animal-assisted interventions. The structure and design of assignments, animal-related aspects and conditions, and education and knowledge are mentioned as generally relevant conditions for ensuring animal welfare from the perspective of animal-assisted intervention practitioners. In addition, different concrete courses of action to ensure animal welfare are described, which are characterized as stopping or changing the setting at different levels. Conclusions: Animal welfare plays a central role for professionals working with animals. However, further studies are necessary in order to record other animal welfare-relevant aspects in the animal-assisted interventions, depending on the respective animal species, and to examine the implementation of animal welfare-related measures. [ABSTRACT FROM AUTHOR]

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Background/Aims: The transient receptor potential cation channel subfamily C member 6 (TRPC6) is a Ca2+-permeable nonselective cation channel and has received recent attention because of its capability to promote chronic kidney disease (CKD). The aims of this study were (i) to examine whether deletion of TRPC6 impacts on renal fibrosis and inflammatory cell infiltration in an early CKD model of unilateral ureter obstruction (UUO) in mice; and (ii) whether TRPC6-deficiency as well as UUO affect the regulation of TRPC expression in murine kidneys. Methods: Wild-type (WT), Trpc6-knockout (Trpc6-/-) and New Zealand obese (NZO) mice underwent sham operation or unilateral ureteral obstruction (UUO). The kidneys were harvested 7 days after surgery. We examined renal fibrosis and inflammatory cell infiltration by histological and immunohistochemical staining. The mRNA expression of TRPC members and markers of fibrosis and inflammation in kidney were assessed by using real-time quantitative reverse transcription PCR. Results: Histological and immunohistochemical analyses revealed less inflammatory cell infiltration (F4/80 and CD3) in UUO kidneys of Trpc6-/- mice compared to UUO kidneys of WT mice as well as less fibrosis. Genomic deletion of TRPC6 also affected the expression of pro-fibrotic genes in UUO Trpc6-/- kidneys compared to UUO WT kidneys while the expression of pro-inflammatory genes did not differ. UUO caused marked up-regulation of Trpc6 and down-regulation of Trpc1 mRNA in kidneys of WT and NZO mice. Trpc3 mRNA expression was significantly elevated in kidneys of Trpc6-/- mice underwent UUO while the levels did not change in kidneys of neither WT nor in NZO mice underwent UUO. Conclusion: TRPC6 contributes to renal fibrosis and immune cell infiltration in the UUO mouse model. Therefore, inhibition of TRPC6 emerges as a promising novel therapeutic strategy for treatment of chronic kidney failure in chronic obstructive nephropathy. However, confounding genomic and non-genomic effects of other TRPC channels should be taken into consideration to fully comprehend the renoprotective potential of targeting TRPC6 therapeutically under chronic kidney damaging conditions. [ABSTRACT FROM AUTHOR]

This case report addresses the problem of underreporting negative results and adverse side effects in animal testing. We present our findings regarding a hyperphagic mouse model associated with unforeseen high mortality. The results outline the necessity of reporting detailed information in the literature to avoid duplication.Obese mouse models are essential in the study of obesity, metabolic syndrome and diabetes mellitus. An experimental model of obesity can be induced by the administration of gold thioglucose (GTG). After transcending the blood-brain barrier, the GTG molecule interacts with regions of the ventromedial hypothalamus, thereby primarily targeting glucose-sensitive neurons. When these neurons are impaired, mice become insensitive to the satiety effects of glucose and develop hyperphagia. In a pilot study for optimising dosage and body weight development, C57BL/6 mice were treated with GTG (0.5 mg/g body weight) or saline, respectively. Animals were provided a physiological amount of standard diet (5 g per animal) for the first 24 hours after treatment to prevent gastric dilatation. Within 24 hours after GTG injection, all GTG-treated animals died of gastric overload and subsequent circulatory shock. Animals developed severe attacks of hyperphagia, and as the amount of provided chow was restricted, mice exhibited unforeseen pica and ingested bedding material. These observations strongly suggest that restricted feeding is contraindicated concerning GTG application. Presumably, the impulse of excessive food intake was a strong driving force. Therefore, the actual degree of suffering in the GTG-induced model of hyperphagia should be revised from moderate to severe. [ABSTRACT FROM AUTHOR]

Concerning standardization of laboratory animal husbandry, only exiguous changes of habitat can potentially influence animal physiology or results of behavioral tests. Routinely, mice chow is dyed when different types of diets are dispensed. Given the fact that the dye itself has no effects on food odor or flavor, we wanted to test the hypothesis that the color of chow has an impact on food uptake in mice.Twelve-week-old male mice of different strains (C57BL/6J, DBA/2J, C3H/HeJ, BALB/cJ; n = 12/strain) were single-housed in PhenoMaster® cages. After acclimatization standard mice chow in different colors was administered. Food intake was monitored as a two-alternative choice test of different color combinations.All animals had an average food intake of 3 g/d and no preferences were observed when a combination of identically colored food was offered. Preference tests yielded significant aversion to blue food and significant attraction to yellow and green food in C57BL/6 and DBA/2J mice. In C3H/HeJ and BALB/cJ mice no color-related pattern occurred.Selected mice strains have known differences concerning functionality of their visual sense. C57BL/6 and DBA/2 mice are considered to be normal sighted at testing age, BALB/c is representative for albino strains and C3H mice carry mutations resulting in retinal alterations. Results suggesting that normal-sighted mice would be selective concerning food color when given the choice. Nevertheless, this does not influence overall quantity of food intake when animals were provided solely with food colored with a single dye. Moreover, visually impaired mice showed no color-related food preferences. [ABSTRACT FROM AUTHOR]

Genetic alterations can unpredictably compromise the wellbeing of animals. Thus, more or less harmful phenotypes might appear in the animals used in research projects even when they are not subjected to experimental treatments. The severity classification of suffering has become an important issue since the implementation of Directive 2010/63/EU on the protection of animals used for scientific purposes. Accordingly, the breeding and maintenance of genetically altered (GA) animals which are likely to develop a harmful phenotype has to be authorized. However, a determination of the degree of severity is rather challenging due to the large variety of phenotypes. Here, the Working Group of Berlin Animal Welfare Officers (WG Berlin AWO) provides field-tested guidelines on severity assessment and classification of GA rodents. With a focus on basic welfare assessment and severity classification we provide a list of symptoms that have been classified as non-harmful, mild, moderate or severe burdens. Corresponding monitoring and refinement strategies as well as specific housing requirements have been compiled and are strongly recommended to improve hitherto applied breeding procedures and conditions. The document serves as a guide to determine the degree of severity for an observed phenotype. The aim is to support scientists, animal care takers, animal welfare bodies and competent authorities with this task, and thereby make an important contribution to a European harmonization of severity assessments for the continually increasing number of GA rodents. [ABSTRACT FROM AUTHOR]

Background: Interleukin-17 (IL-17) is a new pro-inflammatory cytokine involved in immune response and inflammatory disease. The main source of IL-17 is a subset of CD4+ T-helper cells, but is also secreted by non-immune cells. The present study analyzes expression of IL-17 in the time course of acute anti-thy1 glomerulonephritis and the role of IL-17 as a potential link between inflammation and fibrosis. Methods: Anti-thy1 glomerulonephritis was induced into male Wistar rats by OX-7 antibody injection. After that, samples were taken on days 1, 5, 10 (matrix expansion phase), 15 and 20 (resolution phase). PBS-injected animals served as controls. Proteinuria and histological matrixes score served as the main markers for disease severity. In in vitro experiments, NRK-52E cells were used. For cytokine expressions, mRNA and protein levels were analyzed by utilizing RT-PCR, in situ hybridization and immunofluorescence. Results: Highest IL-17 mRNA-expression (6.50-fold vs. con; p<0.05) was found on day 5 after induction of anti-thy1 glomerulonephritis along the maximum levels of proteinuria (113 ± 13 mg/d; p<0.001), histological glomerular-matrix accumulation (82%; p<0.001) and TGF-β1 (2.2-fold; p<0.05), IL-6 mRNA expression (36-fold; p<0.05). IL-17 protein expression co-localized with the endothelial cell marker PECAM in immunofluorescence. In NRK-52E cells, co-administration of TGF-β1 and IL-6 synergistically up-regulated IL-17 mRNA 4986-fold (p<0.001). Conclusions: The pro-inflammatory cytokine IL-17 is up-regulated in endothelial cells during the time course of acute anti-thy1 glomerulonephritis. In vitro, NRK-52E cells secrete IL-17 under pro-fibrotic and pro-inflammatory conditions. [ABSTRACT FROM AUTHOR]

Glucolipotoxic stress has been identified as a key player in the progression of pancreatic β-cell dysfunction contributing to insulin resistance and the development of type 2 diabetes mellitus (T2D). It has been suggested that bioactive lipid intermediates, formed under lipotoxic conditions, are involved in these processes. Here, we show that sphingosine 1-phosphate (S1P) levels are not only increased in palmitate-stimulated pancreatic β-cells but also regulate β-cell homeostasis in a divergent manner. Although S1P possesses a prosurvival effect in β-cells, an enhanced level of the sphingolipid antagonizes insulin-mediated cell growth and survival via the sphingosine 1-phosphate receptor subtype 2 (S1P2) followed by an inhibition of Akt-signaling. In an attempt to investigate the role of the S1P/S1P2 axis in vivo, the New Zealand obese (NZO) diabetic mouse model, characterized by β-cell loss under high-fat diet (HFD) conditions, was used. The occurrence of T2D was accompanied by an increase of plasma S1P levels. To examine whether S1P contributes to the morphologic changes of islets via S1P2, the receptor antagonist JTE-013 was administered. Most interestingly, JTE-013 rescued β-cell damage clearly indicating an important role of the S1P2 in β-cell homeostasis. Therefore, the present study provides a new therapeutic strategy to diminish β-cell dysfunction and the development of T2D. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Enhanced plasma levels of NEFA have been shown to induce hepatic insulin resistance, which contributes to the development of type 2 diabetes. Indeed, sphingolipids can be formed via a de novo pathway from the saturated fatty acid palmitate and the amino acid serine. Besides ceramides, sphingosine 1-phosphate (S1P) has been identified as a major bioactive lipid mediator. Therefore, our aim was to investigate the generation and function of S1P in hepatic insulin resistance. Methods: The incorporation of palmitate into sphingolipids was performed by rapid-resolution liquid chromatography-MS/MS in primary human and rat hepatocytes. The influence of S1P and the involvement of S1P receptors in hepatic insulin resistance was examined in human and rat hepatocytes, as well as in New Zealand obese (NZO) mice. Results: Palmitate induced an impressive formation of extra- and intracellular S1P in rat and human hepatocytes. An elevation of hepatic S1P levels was observed in NZO mice fed a high-fat diet. Once generated, S1P was able, similarly to palmitate, to counteract insulin signalling. The inhibitory effect of S1P was abolished in the presence of the S1P receptor antagonist JTE-013 both in vitro and in vivo. In agreement with this, the immunomodulator FTY720-phosphate, which binds to all S1P receptors except S1P, was not able to inhibit insulin signalling. Conclusions/interpretation: These data indicate that palmitate is metabolised by hepatocytes to S1P, which acts via stimulation of the S1P receptor to impair insulin signalling. In particular, S1P inhibition could be considered as a novel therapeutic target for the treatment of insulin resistance. [ABSTRACT FROM AUTHOR]

Patients treated with the mammalian or mechanistic target of rapamycin (mTOR) inhibitor everolimus in order to slow progression of autosomal-dominant polycystic kidney disease (ADPKD) showed a significant reduction of body weight. Although the detailed mechanism of how mTOR inhibition interferes with body weight regulation is rather unclear, present data suggest that this effect is mediated by both central and peripheral mechanisms. These findings in ADPKD patients are in contrast to well-documented effects of hypothalamic mTOR on regulation of energy homeostasis and eating behavior in rodents. In a number of rodent models, the mTOR inhibitor rapamycin induces increased food intake, which is accompanied by increased body weight. However, animal data are inconsistent. This review highlights some of the regulatory signals and key mechanisms that are important for balancing energy intake and energy expenditure with a special focus on adipose tissue-derived adipokines and their interaction with mTOR regarding local regulation of tissue perfusion and metabolism and overall systemic energy homeostasis. Specifically, clinical aspects of an impaired mTOR signaling pathway regarding the development of obesity and type-2 diabetes mellitus will be discussed. [ABSTRACT FROM AUTHOR]

The lymphocyte migration inhibitor FFY720 attenuates experimental hypertensive nephropathy. Infiltration with lymphocytes is found in both immune and nonimmune chronic kidney diseases. In a rat model of immune-initiated progressive glomerulosclerosis, selective inhibition of lymphocyte infiltration by FTY720 showed significant beneficial effects on renal fibrosis. To test whether this translates into hypertensive nephropathy (HN), the lymphocyte migration inhibitor was administered to rats following ⅚ nephrectomy. Two days after surgery, male Wistar rats were allocated to the following groups: Sham surgery, ⅚ nephrectomy (HN), and HN + FFY720 (0.3 mg/kg body wt). Therapy was continued for 6 wk. Treatment with FFY720 was found to selectively reduce blood lymphocyte counts by 85% (P < 0.001 vs. HN) and renal lymphocyte infiltration (CD-3 positive cells) by 63% (P < 0.01 vs. HN) as was anticipated. Lymphocyte depletion went along with a significant reduction in proteinuria (-28%), whereas hypertensive systemic blood pressure remained unchanged (160 ± 5 vs. 161 ± 5 mmHg, P = not significant). The markedly increased histological tubulointerstitial and glomerular matrix protein accumulation, collagen, laminin, and fibronectin deposition were all significantly impeded in the FTY720-treated animals. The anti-fibrotic effects of FFY720 were paralleled by significant reductions in renal transforming growth factor (TGF)-β overexpression, macrophage infiltration, and cell proliferation. In conclusion, the lymphocyte migration inhibitor FFY720 significantly limits histological and molecular fibrosis in a model of hypertensive nephropathy without affecting increased systemic blood pressure. Prevention of renal lymphocytes' infiltration by FTY720 was followed by significant reductions in TGF-β overexpression, macrophage infiltration, and renal cell proliferation. These results suggest that infiltrating lymphocytes play an active, profibrotic role in the progression of hypertensive renal tissue injury. [ABSTRACT FROM AUTHOR]

In the kidney, ~80% of the filtered phosphate (Pi) is reabsorbed along the proximal tubule. Changes in renal P reabsorption are associated with modulation of the sodium-dependent Pi cotransporter type ha (NaPi-IIa) and type IIc (NaPi-IIc) protein abundance in the brush-border membrane (BBM) of proximal tubule cells. NaPi-IIa is mainly regulated by dietary Pi intake and parathyroid hormone (PTH). The purpose of the present study was to elucidate the effect of alteration in dietary magnesium (Mg2+) intake on renal Pi handling. Urinary Pi excretion and renal expression of NaPi-IIa and NaPi-IIc were analyzed in rats fed a normal (0.2%) or high-Mg2+ (2.5%) diet. A high-Mg2+ diet resulted in decreased renal P, excretion and increased protein expression of NaPi-IIa and NaPi-IIc. Serum FGF-23 (fibroblast growth factor 23) levels were unchanged under a high-Mg2+ diet. Serum PTH levels were slightly decreased under a high-Mg2+ diet. To examine whether the observed changes in renal P, reabsorption are PTH dependent, expression of NaPi-IIa and NaPi-IIc was also analyzed in parathyroidectomized (PTX) rats fed a normal or high-Mg2+ diet. In PTX rats, Mg2+ had no significant effect on renal P excretion or NaPi-IIa protein expression. Mg2+ increased NaPi-IIc protein expression in PTX rats. This experiment shows for the first time on the molecular level how Mg2+ stimulates renal P reabsorption. Under a high-Mg2+ diet, NaPi-IIa expression is dependent on PTH levels, whereas NaPi-IIc expression seems to be independent of PTH levels. [ABSTRACT FROM AUTHOR]

Krämer S, Wang-Rosenke Y, Scholl V, Binder E, Loof T, Khadzhynov D, Kawachi H, Shimizu F, Diekmann F, Budde K, Neumayer H-H, Peters H. Low-dose mTOR inhibition by rapamycin attenuates progression in anti-thyl-induced chronic glomeruloscierosis of the rat. Am J Physiol Renal Physiol 294: F440-F449, 2008. First published December 19, 2007; doi:10.1152/ajprenal.00379.2007.—Treatment options in human mesangioproliferative glomerulonephritis/sclerosis, mostly IgA nephropathy, are limited. Progressive mesangioproliferative nephropathy represents a major cause of end-stage kidney disease. The present study explores the efficacy of low-dose mTOR inhibition by rapamycin in a chronic-progressive model of mesangioproliferative glomerulosclerosis (cGS). cGS was induced by high-dose anti-thyl antibody injection into uninephrectomized rats. Rapamycin administration (2.5 mg·kg-1·body wt-1) was started 10 days after antibody injection and continued until week 20. cGS was characterized by advancing proteinuria, increased blood pressure, marked tubulointerstitial and glomerular fibrosis, cell proliferation and round cell infiltration, and impaired renal function. Kruskal-Wallis and Mann-Whitney U-tests were used for statistical analysis. The course of chronic anti-thyl-induced glomerulosclerosis was significantly attenuated by low-dose rapamycin treatment. In week 20, this was demonstrated by improvements in proteinuria (-38%), systolic blood pressure (-16 mmHg), tubulointerstitial and glomerular histological matrix accumulation (-61 and -24%), transforming growth factor-β1 overexpression (-41 and -47%), collagen I deposition (-53 and -65%), cell proliferation (-90 and -76%), and leukocyte number (macrophages -52 and -53%; lymphocytes -58 and 51%), respectively. Rapamycin improved renal function as well (blood creatinine -0.68 mg/dl, urea -66.7 mg/day, and creatinine clearance +0.13 ml·min-1·100 g body wt-1). In conclusion, low-dose mTOR inhibition by rapamycin limits the progressive course of anti-thyI-induced renal disease toward chronic glomerulosclerosis, tubulointerstitial fibrosis, and renal insufficiency. Renoprotection by rapamycin involved significant beneficial effects on multiple key pathways in the progression of chronic renal disease, i.e., proteinuria, extracellular matrix accumulation, renal cell proliferation, and inflammatory cell infiltration. [ABSTRACT FROM AUTHOR]

FTY720 is a novel immune modulator whose primary action is blood lymphocyte depletion through interaction with sphingosine-1-phosphate (SIP) receptors. The present study analyzes the effect of FTY720 on both the early mesangial cell injury and the subsequent matrix expansion phase of experimental mesangioproliferative glomerulonephritis. Disease was induced by injection of OX-7 anti-thy1 antibody into male Wistar rats. In both protocols, FTY720 administration (0.3 mg/kg body wt) resulted in a selective and very marked reduction in blood lymphocyte count. In the injury experiment, the SIP receptor modulator was given starting 5 days before and continued until 1 day after antibody injection. FTY720 did not significantly affect the degree of anti-thy1-induced mesangial cell lysis and glomerular-inducible nitric oxide production. In the matrix expansion experiment, FTY720 treatment was started 1 day after antibody injection and continued until day 7. In this protocol, the S1P modulator reduced proteinuria, histological matrix expansion, and glomerular protein expression of TGF-β1, fibronectin, and PAI-1. Glomerular collagen III staining intensity was decreased. FTY720 reduced markedly glomerular lymphocyte number per cross section and to a lesser degree macrophage infiltration. In conclusion, FTY720 significantly limits TGF-β1 overexpression and matrix protein expression following induction of acute anti-thy glomerulonephritis, involving reductions in blood and glomerular lymphocyte numbers. The results suggest that lymphocytes actively contribute to matrix expansion in experimental mesangioproliferative glomerulonephritis. Our study expands on findings on FTY720's beneficial effects on tubulointerstitial and functional disease progression previously reported in anti-thy1-induced chronic gbomerulosclerosis. [ABSTRACT FROM AUTHOR]

cGMP serves as the main second messenger of nitric oxide (NO). Antifibrotic effects of enhancing renal cGMP levels have recently been documented in experimental acute anti-Thy-1 glomerulonephritis. The present study compares the effects of the cGMP production-increasing soluble guanylate cyclase (sOC) stimulator BAY 41-2272 with those of the cGMP degradation-limiting phosphodiesterase inhibitor pentoxifylline (PTX) in a progressive model of renal fibrosis. At I wk after induction of anti-Thy-1-induced chronic glomerulosclerosis (cGS), rats were randomly assigned to groups as follows: cGS, cGS + BAY 41-2272 (10 mg·kg body wt-1·day-1), or cGS + PTX (50 mg·kg body wt-1·day-1). BAY 41-2272 and PTX reduced systolic blood pressure significantly. At 16 wk, tubulointerstitial expressions of sGC mRNA and NO-induced cGMP synthesis were increased in untreated cGS animals, whereas their glomerular activity was depressed compared with normal controls. Tubulointerstitial and glomerular cGMP production in response to NO were significantly enhanced in animals treated with BAY 41-2272, but not in those treated with PTX. BAY 41-2272 administration resulted in marked reductions of glomerular and tubulointerstitial histological matrix accumulation, expression of TGF-β1 and fibronectin, macrophage infiltration, and cell proliferation as well as improved renal function. In contrast, only moderate and nonsignificant renoprotective changes were observed in the cOS + PTX group. In conclusion, increasing renal cGMP production through BAY 41-2272 significantly improved renal NO-cGMP signaling and limited progression in anti-Thy-1-induced chronic renal fibrosis, whereas inhibition of cGMP degradation by PTX was only moderately effective. The findings indicate that pharmacological enhancement of renal cGMP levels by sGC stimulation represents a novel and effective antifibrotic approach in progressive kidney disorders. [ABSTRACT FROM AUTHOR]

Tubulointerstitial inflammation and fibrosis are hallmarks of chronic progressive renal diseases. To characterize the functional interaction between cell infiltration and matrix expansion, this study compared the immunosuppressant mycophenolate mofetil (MMF), intended as primarily anti-inflammatory intervention, the angiotensin-converting enzyme inhibitor enalapril, intended as primarily an anti-fibrotic drug, and a combination of both as anticipated anti-inflammatory/anti-fibrotic intervention. The model used was anti-thy1-induced chronic-progressive glomerulosclerosis (cGS) in the rat, where a brief anti-thy1-induced glomerular injury progresses spontaneously toward tubulointerstitial fibrosis and renal insufficiency, cGS was induced by injection of anti-thy 1 antibody into uninephrectomized Wistar rats. One week after disease induction, animals were randomly assigned to the following groups: cGS, cGS plus MMF (20 mg·kg body wt-1·day-1), cGS plus high-dose enalapril (12 mg·kg body wt-1·day-1), and cGS plus both. At week 16 after disease induction, MMF or enalapril alone reduced signs of chronic renal disease significantly and similarly compared with the untreated cGS group. Variables measured included proteinuria, blood pressure, tubulointerstitial and glomerular matrix accumulation, expression of transforming growth factor-β1, fibronectin, and plasminogen activator inhibitor-1, infiltration of lymphocytes and macrophages, plasma creatinine and urea levels, and glomerular filtration rate. Combined MMF and enalapril treatment was not superior to single therapy. In conclusion, MMF slows the progression of chronic renal fibrosis and renal insufficiency as effectively as high-dose enalapril in the anti-thy1-induced chronic-progressive glomerulosclerosis model. The dual anti-inflammatory/anti-fibrotic intervention does not yield additive renoprotective effects, indicating that MMF and enalapril interfere with similar or very closely related pathways involved in progression of renal disease. [ABSTRACT FROM AUTHOR]

Moderate alcohol consumption has shown beneficial effects in experimental and human cardiovascular disease. With the use of rat models of acute and chronic progressive anti-thyl glomerulonephritis (GN), we tested the hypothesis that moderate alcohol intake is protective in renal fibrotic disease. In acute anti-thy1 GN, untreated nephritic rats showed marked mesangial cell lysis and induced nitric oxide production at day I and high proteinuria, glomerular matrix accumulation, and transforming growth factor (TGF)β[sub 1], fibronectin, and plasminogen activator inhibitor (PAI)-1 expression at day 7 after disease induction, respectively. In animals 15 wk after induction of chronic progressive antithy1 GN, disease was characterized by significantly reduced renal function, persisting albuminuria as well as increased glomerular and tubulointerstitial matrix expansion, TGF-β[sub 1], fibronectin, and PAI-1 protein expression. In both anti-thy1 GN models, an ethanol intake of ∼2 ml per day and animal was achieved, however, disease severity was not significantly altered by moderate alcohol consumption in any of the protocols. In conclusion, moderate alcohol intake does not influence renal matrix protein production and accumulation in acute and chronic progressive anti-thy1 glomerulofibrosis. The study suggests that, in contrast to cardiovascular disorders, moderate alcohol consumption might not provide specific protection in renal fibrotic disease. [ABSTRACT FROM AUTHOR]

An abstract of the paper "Activation of the Nitric Oxide-cGMP Signaling Pathway Precedes Resolution in Acute Anti-thy1 Glomerulonephritis," by Yingrui Wang-Rosenke, Tanja Loof and colleagues is presented.

An abstract of the article "Enhancing cGMP in anti-thy 1-induced, chronic-progressive glomerulosclerosis: sGC stimulation versus PDEs inhibition," by Yingrui Wang, Stephanie Krämer and colleagues is presented.