Mesenchymal stem cells as therapeutic candidates for halting the progression of diabetic nephropathy

Mesenchymal stem cells (MSCs) possess pleiotropic properties that include immunomodulation, inhibition of apoptosis, fibrosis and oxidative stress, secretion of trophic factors, and enhancement of angiogenesis. These properties provide a broad spectrum for their potential in a wide range of injuries and diseases, including diabetic nephropathy (DN). MSCs are characterized by adherence to plastic, expression of the surface molecules CD73, CD90, and CD105 in the absence of CD34, CD45, HLA-DR, and CD14 or CD11b and CD79a or CD19 surface molecules, and multidifferentiation capacity in vitro. MSCs can be derived from many tissue sources, consistent with their broad, possibly ubiquitous distribution. This article reviews the existing literature and knowledge of MSC therapy in DN, as well as the most appropriate rodent models to verify the therapeutic potential of MSCs in DN setting. Some preclinical relevant studies are highlighted and new perspectives of combined therapies for decreasing DN progression are discussed. Hence, improved comprehension and interpretation of experimental data will accelerate the progress towards clinical trials that should assess the feasibility and safety of this therapeutic approach in humans. Therefore, MSC-based therapies may bring substantial benefit for patients suffering from DN.FAPESP (Fundacao de Amparo a Pesquisa do Estado de Sao Paulo/Sao Paulo Research Foundation) [2013/19560-6]CNPq (Conselho Nacional de Desenvolvimento Cientifico e Tecnologico/National Counsel of Technological and Scientific Development) [456959/2013-0]EFSD (European Foundation for the Study of Diabetes)Sociedade Beneficente Albert Einstein, Albert Einstein Hospital, 05652 São Paulo, SP, Brazil[University of São Paulo, 01246 São Paulo, SP, BrazilFederal University of São Paulo, 04023 São Paulo, SP, BrazilFederal University of São Paulo, 04023 São Paulo, SP, BrazilFAPESP: 2013/19560-6CNPq: 456959/2013-0Web of Scienc

Renin angiotensin system and cardiac hypertrophy after sinoaortic denervation in rats

OBJECTIVE: The aim of this study was to evaluate the role of angiotensin I, II and 1-7 on left ventricular hypertrophy of Wistar and spontaneously hypertensive rats submitted to sinoaortic denervation. METHODS: Ten weeks after sinoaortic denervation, hemodynamic and morphofunctional parameters were analyzed, and the left ventricle was dissected for biochemical analyses. RESULTS: Hypertensive groups (controls and denervated) showed an increase on mean blood pressure compared with normotensive ones (controls and denervated). Blood pressure variability was higher in denervated groups than in their respective controls. Left ventricular mass and collagen content were increased in the normotensive denervated and in both spontaneously hypertensive groups compared with Wistar controls. Both hypertensive groups presented a higher concentration of angiotensin II than Wistar controls, whereas angiotensin 1-7 concentration was decreased in the hypertensive denervated group in relation to the Wistar groups. There was no difference in angiotensin I concentration among groups. CONCLUSION: Our results suggest that not only blood pressure variability and reduced baroreflex sensitivity but also elevated levels of angiotensin II and a reduced concentration of angiotensin 1-7 may contribute to the development of left ventricular hypertrophy. These data indicate that baroreflex dysfunction associated with changes in the renin angiotensin system may be predictive factors of left ventricular hypertrophy and cardiac failure

Baroreceptor influence on the evolution of diabetic cardiomyopathy and nephropathy in rats

Está bem documentada a importância da disfunção autonômica na evolução das complicações do Diabetes. Adicionalmente, novas e consistentes evidências indicam que o controle reflexo da circulação comandado pelos baroreceptores poderia ser um marcador prognóstico precoce no Diabete melito, clínico e experimental. No presente projeto, testamos a hipótese de que a disfunção barorreflexa interfere no desenvolvimento da nefropatia e cardiomiopatia diabética por alterar a modulação autonômica comandada pelos barorreceptores arteriais sobre vasos e coração. Foram utilizados ratos Wistar machos (230 a 260g) divididos em 4 grupos experimentais: controle (GC, n=9), diabético (GD, n=11), desnervado (GCD, n=9) e desnervado diabético (GDD, n=8). Após 7 dias de desnervação sinoaórtica, foi realizada a indução do diabetes (DM) por estreptozotocina (STZ). Foram realizadas avaliações metabólicas, teste de tolerância a glicose e avaliações ecocardiográficas durante a terceira semana do protocolo. A partir dos 28 dias de protocolo foram realizados registros diretos da pressão arterial (PA) e avaliações da sensibilidade barorreflexas, da modulação autonômica cardiovascular (variabilidade da freqüência cardíaca e da PA sistólica), análise dos fluxos sanguíneos regionais e avaliações renais ex vivo. Os grupos diabéticos (GD e GDD) apresentaram aumento da glicemia e redução do peso corporal, da PA e da freqüência cardíaca quando comparados com os grupos não diabéticos (GC e GCD). Os grupos diabéticos apresentaram uma maior área de resposta sob a curva de resposta glicêmica quando comparados aos grupos controle, indicando assim uma intolerância maior a glicose. Nos parâmetros morfométricos, o septo interventricular (SIVDIA) mostrou-se menor nos grupos diabéticos quando comparados ao GC. A parede posterior do ventrículo esquerdo (PPDIA) mostrou-se diminuída somente no grupo diabético. Com relação ao tamanho da cavidade do ventrículo esquerdo na diástole (VEDIA), observou-se uma tendência a aumento em todos os grupos quando comparados ao controle. A massa do ventrículo esquerdo (MVE) foi menor no grupo diabético em relação ao controle e maior nos grupos submetidos à DSA quando comparados ao GC. A função sistólica foi avaliada pela fração de ejeção (FE), na qual não foi observada diferença entre os grupos estudados. A função diastólica foi avaliada pelo tempo de relaxamento isovolumétrico (TRIV) que foi maior no grupo diabético quando comparado ao controle. Já o grupo desnervado apresentou valores próximos ao do GC. Entretanto, o grupo desnervado diabético apresentou valores menores de TRIV quando comparado aos animais apenas diabéticos. Disfunção autonômica, avaliada pela sensibilidade barorreflexa, pela variabilidade da FC (VFC) e da PA sistólica (VPAS), foram observadas nos grupos GD, GCD e GDD em relação ao grupo C. Os fluxos sanguíneos analisados nesse protocolo (coronariano, pulmonar, renal e muscular) apresentaram-se reduzidos em todos os grupos experimentais quando comparados ao GC. O grupo submetido à SAD mostrou uma redução mais acentuada em todos os fluxos sanguíneos estudados. A resistência vascular periférica total encontra-se aumentada em todos os grupos analisados com um aumento maior nos grupos diabéticos. O débito cardíaco mostrou-se reduzido em todos os grupos estudados, em especial no grupo desnervado diabético, quando comparados com o GC. Com relação ao índice cardíaco, também observamos uma redução em todos os grupos, com uma redução maior nos grupos diabéticos sendo que a desnervação não foi capaz de atenuar essa redução no grupo desnervado diabético. A avaliação renal mostrou um aumento da pressão de perfusão do GD, acompanhado por um aumento significativo na resistência vascular renal, no fluxo urinário, no ritmo de filtração glomerular. Dessa forma, os resultados obtidos no presente trabalho fornecem evidencias de que o papel homeostático do baroreflexo é essencial no curso das alterações cardíacas e renais tanto em animais normoglicêmicos como nos hiperglicêmicos, por sua ação não só no controle das variações momento a momento (labilidade) como também interferindo em alterações sustentadas da PA, como observado nesse trabalho. Esses resultados poderão dar suporte a estudos populacionais que associam maior sensibilidade do baroreflexo com melhor prognóstico e sobrevida após evento cardiovascular em indivíduos diabéticosIt is well documented the importance of autonomic dysfunction in microvascular complications of diabetes. Additionally, new and consistent evidence indicates that the reflex control of movement is controlled by the baroreceptors could be an early prognostic marker in diabetes mellitus, clinical and experimental. In this project, we tested the hypothesis that baroreflex dysfunction interferes with the development of nephropathy and diabetic cardiomyopathy by altering the autonomic modulation controlled by the arterial baroreceptors on heart and blood vessels. We used male Wistar rats (230 to 260g) were divided into four groups: control group (n = 9), diabetic (GD, n = 11), denervated (GCD, n = 9) and diabetic denervated (GDD, n = 8). After 7 days of sinoaortic denervation was performed we induced diabetes (DM) by streptozotocin (STZ). We evaluated metabolic, glucose tolerance test and echocardiographic evaluations during the third week of the protocol. After 28 days of protocol records were taken direct blood pressure (BP) and baroreflex sensitivity assessments of cardiovascular autonomic (heart rate variability and systolic BP), regional blood flow analysis and evaluations kidney ex vivo. Diabetic groups (GD and GDD) had higher blood glucose and reduced body weight, blood pressure and heart rate when compared with non-diabetic groups (GC and GCD). Diabetic groups showed a larger response area under the glycemic response curve when compared to control groups, thus indicating an increased glucose intolerance. The morphometric parameters, interventricular septum (IVSD) was lower in both diabetic groups compared to CG. The back wall of the left ventricle (PPDIA) was reduced only in diabetic mice. Regarding the size of the cavity of the left ventricle during diastole (Vedia), there was a tendency to increase in all groups compared to control. The left ventricular mass (LVM) was lower in the diabetic group compared to control, and higher in the groups submitted to DSA when compared to CG. Systolic function was evaluated by ejection fraction (EF), in which there was no difference between groups. Diastolic function was evaluated by isovolumic relaxation time (IVRT) was greater in the diabetic group compared to control. The denervated group showed similar to the CG. However, the denervated diabetic group showed lower values of IVRT as compared to diabetic animals only. Autonomic dysfunction, as assessed by baroreflex sensitivity by HR variability (HRV) and systolic (VPAS) were observed in groups GD, GCD and GDD than in group C. The blood flows analyzed in this protocol (coronary, pulmonary, kidney and muscle) were reduced in all experimental groups compared to CG. The group submitted to SAD showed a marked reduction in all blood flows studied. The total peripheral vascular resistance is increased in all groups with a greater increase in the diabetic group. Cardiac output was reduced in all groups, especially in denervated diabetic group compared with the GC. With respect to cardiac index, we also observed a reduction in all groups, with a greater reduction in the diabetic group and that denervation was not able to mitigate this reduction in denervated diabetic group. The evaluation showed an increase in renal perfusion pressure of the GD, accompanied by a significant increase in renal vascular resistance, urinary flow, the glomerular filtration rate. Thus, the results obtained in this study provide evidence that the homeostatic role of the baroreflex is essential in the course of changes in both heart and kidney as in hyperglycemic animals normoglycemic by acting not only in control of changes moment to moment (lability) as well as interfering with sustained changes in BP, as observed in this study. These results could support population studies linking higher sensitivity of the baroreflex with a better prognosis and survival after a cardiovascular event in diabetic subject

Mesenchymal Stem Cells as Therapeutic Candidates for Halting the Progression of Diabetic Nephropathy

Mesenchymal stem cells (MSCs) possess pleiotropic properties that include immunomodulation, inhibition of apoptosis, fibrosis and oxidative stress, secretion of trophic factors, and enhancement of angiogenesis. These properties provide a broad spectrum for their potential in a wide range of injuries and diseases, including diabetic nephropathy (DN). MSCs are characterized by adherence to plastic, expression of the surface molecules CD73, CD90, and CD105 in the absence of CD34, CD45, HLA-DR, and CD14 or CD11b and CD79a or CD19 surface molecules, and multidifferentiation capacity in vitro. MSCs can be derived from many tissue sources, consistent with their broad, possibly ubiquitous distribution. This article reviews the existing literature and knowledge of MSC therapy in DN, as well as the most appropriate rodent models to verify the therapeutic potential of MSCs in DN setting. Some preclinical relevant studies are highlighted and new perspectives of combined therapies for decreasing DN progression are discussed. Hence, improved comprehension and interpretation of experimental data will accelerate the progress towards clinical trials that should assess the feasibility and safety of this therapeutic approach in humans. Therefore, MSC-based therapies may bring substantial benefit for patients suffering from DN

Exercise training associated with estrogen therapy induced cardiovascular benefits after ovarian hormones deprivation

Menopause is recognized as a period of increased risk for coronary heart disease. Although the benefits of exercise training in lowering cardiovascular risk factors are well established, the risks and benefits of hormone therapy have been questioned. The purpose of the present study was to investigate the effects of estrogen therapy (HT) associated or not with exercise training (ET) in autonomic cardiovascular control in ovariectomized (OVX) rats. Female rats were divided into: control, OVX, OVX+HT, OVX+ET and OVX+HT+ET. HT was performed using a 0.25 mg 8-weeks sustained release pellet. Trained groups were submitted to an 8-week exercise training protocol on treadmill. Baroreflex sensitivity (BRS) was evaluated by heart rate responses to arterial pressure (AP) changes, and vagal and sympathetic tonus by pharmacological blockade. Ovariectomy induced an AP increase (123 +/- 2 mmHg vs. 108 +/- 2 mmHg), BRS impairment (similar to 69%), sympathetic activation (similar to 100%) and vagal tonus reduction (similar to 77%) compared to controls. HT or ET normalized the changes in parasympathetic tonus. However, only the association HT + ET was able to promote normalization of AP, BRS and sympathetic tonus, as compared to controls. These results indicate that ET induces cardiovascular and autonomic benefits in OVX rats under HT, suggesting a positive role of this association in the management of cardiovascular risk factor in postmenopausal women. (C) 2009 Elsevier Ireland Ltd. All rights reserved.FAPESP Fundacao de Amparo a Pesquisa do Estado de Sao Paulo[07/57595-5]FAPESP Fundacao de Amparo a Pesquisa do Estado de Sao Paulo[09/06865-8]Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES)Conselho Nacional de Desenvolvimento Cientifico a Tecnologico (CNPq

Relationship between renal and cardiovascular changes in a murine model of glucose intolerance

Nutrition is an important variable which may affect the risk for renal disease. We previously showed that a high fructose diet in mice produced hypertension and sympathetic activation [8]. The purpose of this study was to determine if a fructose diet altered renal function. A high fructose diet for 12 weeks impaired glucose tolerance, but caused no change in body weight, blood glucose or plasma insulin. Impairment in renal function was documented by the almost two fold increase in urinary protein excretion (Control: 6.6 ± 0.6 vs. Fructose: 15.0 ± 0.7 mmol protein/mmol creatinine; p \u3c 0.05) which was also accompanied by increases in urinary volume. The diet produced little change in renal histology, kidney weight or kidney weight/body weight ratio. Urinary excretion of angiotensin II/creatinine (Control: 78.9 ± 16.6 vs. Fructose: 80.5 ± 14.2 pg/mmol) and renal angiotensin converting enzyme activity (Control: 9.2 ± 1.6 vs. Fructose: 7.6 ± 1.0 ACE units) were not different between groups. There was a positive correlation between mean arterial pressure (r = 0.7, p = 0.01), blood pressure variability (BPV) (r = 0.7, p = 0.02), low frequency BPV component (r = 0.677, p = 0.03) and urinary protein excretion. Results show that consumption of a high fructose diet in mice had deleterious effects on renal function, which were correlated with cardiovascular changes

Relationship between renal and cardiovascular changes in a murine model of glucose intolerance

Nutrition is an important variable which may affect the risk for renal disease. We previously showed that a high fructose diet in mice produced hypertension and sympathetic activation [8]. The purpose of this study was to determine if a fructose diet altered renal function. A high fructose diet for 12 weeks impaired glucose tolerance, but caused no change in body weight, blood glucose or plasma insulin. Impairment in renal function was documented by the almost two fold increase in urinary protein excretion (Control: 6.6 ± 0.6 vs. Fructose: 15.0 ± 0.7 mmol protein/mmol creatinine; p \u3c 0.05) which was also accompanied by increases in urinary volume. The diet produced little change in renal histology, kidney weight or kidney weight/body weight ratio. Urinary excretion of angiotensin II/creatinine (Control: 78.9 ± 16.6 vs. Fructose: 80.5 ± 14.2 pg/mmol) and renal angiotensin converting enzyme activity (Control: 9.2 ± 1.6 vs. Fructose: 7.6 ± 1.0 ACE units) were not different between groups. There was a positive correlation between mean arterial pressure (r = 0.7, p = 0.01), blood pressure variability (BPV) (r = 0.7, p = 0.02), low frequency BPV component (r = 0.677, p = 0.03) and urinary protein excretion. Results show that consumption of a high fructose diet in mice had deleterious effects on renal function, which were correlated with cardiovascular changes