Bone marrow mononuclear cells attenuate fibrosis development after severe acute kidney injury.

One of the early phases that lead to fibrosis progression is inflammation. Once this stage is resolved, fibrosis might be prevented. Bone marrow mononuclear cells (BMMCs) are emerging as a new therapy for several pathologies, including autoimmune diseases, because they enact immunosuppression. In this study we aimed to evaluate the role of BMMC administration in a model of kidney fibrosis induced by an acute injury. C57Bl6 mice were subjected to unilateral severe ischemia by clamping the left renal pedicle for 1h. BMMCs were isolated from femurs and tibia, and after 6h of reperfusion, 1 x 10(6) cells were administrated intraperitoneally. At 24h after surgery, treated animals showed a significant decrease in creatinine and urea levels when compared with untreated animals. Different administration routes were tested. Moreover, interferon (IFN) receptor knockout BMMCs were used, as this receptor is necessary for BMMC activation. Labeled BMMCs were found in ischemic kidney on FACS analysis. This improved outcome was associated with modulation of inflammation in the kidney and systemic modulation, as determined by cytokine expression profiling. Despite non-amelioration of functional parameters, kidney mRNA expression of interleukin (IL)-6 at 6 weeks was lower in BMMC-treated animals, as were levels of collagen 1, connective tissue growth factor (CTGF), transforming growth factor-beta (TGF-beta) and vimentin. Protective molecules, such as IL-10, heme oxygenase 1 (HO-1) and bone morphogenetic 7 (BMP-7), were increased in treated animals after 6 weeks. Moreover, Masson and Picrosirius red staining analyses showed less fibrotic areas in the kidneys of treated animals. Thus, early modulation of inflammation by BMMCs after an ischemic injury leads to reduced fibrosis through modulation of early inflammation.

Acute effects of power and resistance exercises on hemodynamic measurements of older women.

PURPOSE: The purpose of this study was to compare the acute effects of resistance training (RT) and power training (PT) on the hemodynamic parameters and nitric oxide (NO) bioavailability of older women. MATERIALS AND METHODS: A randomized experimental design was used in this study. Twenty-one older women (age: 67.1±4.6 years; body mass index: 28.03±4.9 kg/m2; systolic blood pressure: 135.1±21.1 mmHg) were recruited to participate in this study. Volunteers were randomly allocated into PT, RT, and control session (CS) groups. The PT and RT groups underwent a single session of physical exercise equalized by training volume, characterized by 3 sets of 8-10 repetitions in 8 different exercises. However, RT group performed exercise at a higher intensity (difficult) than PT (moderate) group. On the other hand, concentric contractions were faster in PT group than in RT group. Hemodynamic parameters and saliva samples (for NO quantification) were collected before and during an hour after exercise completion. RESULTS: Results demonstrated post-exercise hypotension during 35 minutes in the PT when compared to rest period (P=0.001). In turn, RT showed decreased heart rate and double product (P<0.001) during the whole evaluation period after exercise completion compared with the rest period. NO levels increased in the PT and RT during the whole evaluation period in relation to rest period. However, there were no differences between PT, RT, and CS regarding hemodynamic and NO evaluations. CONCLUSION: Data indicate that an acute session of power and resistance exercise can be effective to cause beneficial changes on hemodynamic parameters and NO levels in older women.

Adipose Tissue-Derived Stem Cells Reduce Acute and Chronic Kidney Damage in Mice.

Acute and chronic kidney injuries (AKI and CKI) constitute syndromes responsible for a large part of renal failures, and are today still associated with high mortality rates. Given the lack of more effective therapies, there has been intense focus on the use stem cells for organ protective and regenerative effects. Mesenchymal stem cells (MSCs) have shown great potential in the treatment of various diseases of immune character, although there is still debate on its mechanism of action. Thus, for a greater understanding of the role of MSCs, we evaluated the effect of adipose tissue-derived stem cells (AdSCs) in an experimental model of nephrotoxicity induced by folic acid (FA) in FVB mice. AdSC-treated animals displayed kidney functional improvement 24h after therapy, represented by reduced serum urea after FA. These data correlated with cell cycle regulation and immune response modulation via reduced chemokine expression and reduced neutrophil infiltrate. Long-term analyses, 4 weeks after FA, indicated that AdSC treatment reduced kidney fibrosis and chronic inflammation. These were demonstrated by reduced interstitial collagen deposition and tissue chemokine and cytokine expression. Thus, we concluded that AdSC treatment played a protective role in the framework of nephrotoxic injury via modulation of inflammation and cell cycle regulation, resulting in reduced kidney damage and functional improvement, inhibiting organ fibrosis and providing long-term immune regulation.

Adipose tissue-derived stem cell treatment prevents renal disease progression.

Adipose tissue-derived stem cells (ASCs) are an attractive source of stem cells with regenerative properties that are similar to those of bone marrow stem cells. Here, we analyze the role of ASCs in reducing the progression of kidney fibrosis. Progressive renal fibrosis was achieved by unilateral clamping of the renal pedicle in mice for 1 h; after that, the kidney was reperfused immediately. Four hours after the surgery, 2 × 10(5) ASCs were intraperitoneally administered, and mice were followed for 24 h posttreatment and then at some other time interval for the next 6 weeks. Also, animals were treated with 2 × 10(5) ASCs at 6 weeks after reperfusion and sacrificed 4 weeks later to study their effect when interstitial fibrosis is already present. At 24 h after reperfusion, ASC-treated animals showed reduced renal dysfunction and enhanced regenerative tubular processes. Renal mRNA expression of IL-6 and TNF was decreased in ASC-treated animals, whereas IL-4, IL-10, and HO-1 expression increased despite a lack of ASCs in the kidneys as determined by SRY analysis. As expected, untreated kidneys shrank at 6 weeks, whereas the kidneys of ASC-treated animals remained normal in size, showed less collagen deposition, and decreased staining for FSP-1, type I collagen, and Hypoxyprobe. The renal protection seen in ASC-treated animals was followed by reduced serum levels of TNF-α, KC, RANTES, and IL-1α. Surprisingly, treatment with ASCs at 6 weeks, when animals already showed installed fibrosis, demonstrated amelioration of functional parameters, with less tissue fibrosis observed and reduced mRNA expression of type I collagen and vimentin. ASC therapy can improve functional parameters and reduce progression of renal fibrosis at early and later times after injury, mostly due to early modulation of the inflammatory response and to less hypoxia, thereby reducing the epithelial-mesenchymal transition.

Role of adipose tissue-derived stem cells in the progression of renal disease.

OBJECTIVE: To analyze the role of adipose tissue-derived stem cells in reducing the progression of renal fibrosis. METHODS: adipose tissue-derived stem cells were isolated from C57Bl/6 mice and characterized by cytometry and differentiation. Renal fibrosis was established after unilateral clamping of the renal pedicle for 1 hour. Four hours after reperfusion, 2.105 adipose tissue-derived stem cells were administered intraperitoneally and the animals were followed for 24 hours during 6 weeks. In another experimental group, 2.105adipose tissue-derived stem cells were administered only after 6 weeks of reperfusion, and they were euthanized and studied 4 weeks later. Twenty-four hours after reperfusion, the animals treated with adipose tissue-derived stem cells displayed reduced renal and tubular dysfunction and an increase of the regenerative process. Renal expression of IL-6 and TNF mRNA were decreased in the animals treated with adipose tissue-derived stem cells, while the levels of IL-4, IL-10, and HO-1 were increased, despite the fact that adipose tissue-derived stem cells were not observed in the kidneys via SRY analysis. RESULTS: In 6 weeks, the kidneys of non-treated animals decreased in size, and the kidneys of the animals treated with adipose tissue-derived stem cells remained at normal size and display less deposition of type 1 collagen and FSP-1. The renal protection observed in animals treated with adipose tissue-derived stem cells was followed by a drop in serum levels of TNF-α, KC, RANTES, and IL-1a. Treatment with adipose tissue-derived stem cells after 6 weeks, when the animals already displayed established fibrosis, demonstrated an improvement in functional parameters and less fibrosis analyzed by Picrosirius stain, as well as a reduction of the expression of type 1 collagen and vimentin mRNA. CONCLUSION: Treatment with adipose tissue-derived stem cells may deter the progression of renal fibrosis by modulation of the early inflammatory response, likely via reduction of the epithelial-mesenchymal transition.

Role of adipose tissue-derived stem cells in the progression of renal disease / Papel das células-tronco derivadas do tecido adiposo na progressão da doença renal

Objective: To analyze the role of adipose tissue-derived stem cells in reducing the progression of renal fibrosis. Methods: adipose tissue-derived stem cells were isolated from C57Bl/6 mice and characterized by cytometry and differentiation. Renal fibrosis was established after unilateral clamping of the renal pedicle for 1 hour. Four hours after reperfusion, 2.105 adipose tissue-derived stem cells were administered intraperitoneally and the animals were followed for 24 hours during 6 weeks. In another experimental group, 2.105 adipose tissue-derived stem cells were administered only after 6 weeks of reperfusion, and they were euthanized and studied 4 weeks later. Twenty-four hours after reperfusion, the animals treated with adipose tissue-derived stem cells displayed reduced renal and tubular dysfunction and an increase of the regenerative process. Renal expression of IL-6 and TNF mRNA were decreased in the animals treated with adipose tissue-derived stem cells, while the levels of IL-4, IL-10, and HO-1 were increased, despite the fact that adipose tissue-derived stem cells were not observed in the kidneys via SRY analysis. Results: In 6 weeks, the kidneys of non-treated animals decreased in size, and the kidneys of the animals treated with adipose tissue-derived stem cells remained at normal size and display less deposition of type 1 collagen and FSP-1. The renal protection observed in animals treated with adipose tissue-derived stem cells was followed by a drop in serum levels of TNF-alpha, KC, RANTES, and IL-1a. Treatment with adipose tissue-derived stem cells after 6 weeks, when the animals already displayed established fibrosis, demonstrated an improvement in functional parameters and less fibrosis analyzed by Picrosirius stain, as well as a reduction of the expression of type 1 collagen and vimentin mRNA.

Objetivo: Analisar o papel das células-tronco derivadas do tecido adiposo na redução da progressão da fibrose renal. Métodos: células-tronco derivadas do tecido adiposo foram isoladas de camundongos C57Bl/6 e caracterizadas por citometria e diferenciação. Fibrose renal foi instaurada após clampeamento unilateral do pedículo renal por 1 hora. Após 4 horas de reperfusão, 2.105 células-tronco derivadas do tecido adiposo foram administradas por via intraperitoneal, e os animais foram acompanhados por 24 horas e 6 semanas. Em outro grupo de experimentos, 2.105 células-tronco derivadas do tecido adiposo foram administradas somente após 6 semanas de reperfusão, e os animais foram sacrificados e estudados 4 semanas mais tarde. Após 24 horas da reperfusão, animais tratados com células-tronco derivadas do tecido adiposo apresentaram reduzida disfunção renal e tubular, além de aumento do processo regenerativo. Expressão renal de RNAm de IL-6 e TNF foi diminuída nos animais tratados com células-tronco derivadas do tecido adiposo, enquanto IL-4, IL-10 e HO-1 foram aumentadas, apesar de células-tronco derivadas do tecido adiposo não serem observadas nos rins por meio da análise SRY. Resultados: Em 6 semanas, os rins dos animais não tratados diminuíram; no entanto, os rins dos animais tratados com células-tronco derivadas do tecido adiposo permaneceram com o tamanho normal e apresentaram menor deposição de colágeno tipo 1 e FSP-1. Proteção renal observada em animais tratados com células-tronco derivadas do tecido adiposo foi seguida por redução nos níveis séricos de TNF-alfa, KC, RANTES e IL-1a. O tratamento com células-tronco derivadas do tecido adiposo após 6 semanas, quando os animais já apresentavam fibrose instalada, demonstrou melhora em parâmetros funcionais e menos fibrose, analisada pela coloração de Picrosirius, e redução da expressão de RNAm de colágeno tipo I e vimentina.