Catecholamines production by kidney tissue and mesangial cell culture is differentially modulated by diabetes / A produção de catecolaminas pelo tecido renal e a cultura de células mesangiais é modulada diferencialmente pelo diabetes

Abstract Introduction: According to the International Diabetes Federation, the number of people with diabetes mellitus may reach 700 million in 2045. Catecholamines are involved in the regulation of several kidney functions. This study investigates the effects of hyperglycemia on catecholamines' metabolism in kidney tissue from control, diabetic, and insulin-treated diabetic rats, both in vivo and in vitro. Methods: Male Wistar-Hannover rats were randomized into: control, diabetic, and insulin-treated diabetic groups. Diabetes was induced by a single injection of streptozotocin, and diabetic treated group also received insulin. After 60 days, blood and kidney tissue from all groups were collected for catecholamines' quantification and mesangial cells culture. Results: diabetic rats had lower body weight, hyperglycemia, and increase water intake and diuresis. Additionally, diabetes promoted a sharp decrease in creatinine clearance compared to control group. Regarding the whole kidney extracts, both diabetic groups (treated and non-treated) had significant reduction in norepinephrine concentration. In mesangial cell culture, catecholamines' concentration were lower in the culture medium than in the intracellular compartment for all groups. Norepinephrine, epinephrine, and dopamine medium levels were increased in the diabetic group. Conclusion: The major finding of the present study was that 8 weeks of diabetes induction altered the kidney catecholaminergic system in a very specific manner, once the production of catecholamines in the excised kidney tissue from diabetic rats was differentially modulated as compared with the production and secretion by cultured mesangial cells.

Resumo Introdução: Segundo a Federação Internacional de Diabetes, o número de pessoas com diabetes mellitus pode chegar a 700 milhões em 2045. As catecolaminas estão envolvidas na regulação de várias funções renais. Este estudo investiga os efeitos da hiperglicemia no metabolismo das catecolaminas no tecido renal de ratos controle, diabéticos e diabéticos tratados com insulina, tanto in vivo como in vitro. Métodos: Os ratos Wistar-Hannover machos foram randomizados em: grupos controle, diabéticos e diabéticos tratados com insulina. O diabetes foi induzido por uma única injeção de estreptozotocina, e o grupo diabético tratado também recebeu insulina. Após 60 dias, sangue e tecido renal dos grupos foram coletados para quantificação de catecolaminas e cultura de células mesangiais. Resultados: ratos diabéticos apresentaram peso corporal mais baixo, hiperglicemia, e aumento da ingestão de água e diurese. Ademais, o diabetes promoveu uma redução acentuada na depuração de creatinina comparado com o grupo controle. Quanto aos extratos de rim total, ambos os grupos diabéticos (tratados/não tratados) tiveram redução significativa na concentração de noradrenalina. Na cultura de células mesangiais, a concentração de catecolaminas foi menor no meio de cultura do que no compartimento intracelular para todos os grupos. Níveis médios de noradrenalina, adrenalina e dopamina estavam aumentados no grupo diabético. Conclusão: O principal achado deste estudo foi que 8 semanas de indução de diabetes alteraram o sistema catecolaminérgico renal de maneira muito específica, já que a produção de catecolaminas no tecido renal excisado de ratos diabéticos foi modulada diferencialmente comparada com produção e secreção por células mesangiais cultivadas.

Resistance exercise shifts the balance of renin-angiotensin system toward ACE2/Ang 1-7 axis and reduces inflammation in the kidney of diabetic rats.

AIMS: We aimed to determine whether resistance training (RT) regulates renal renin-angiotensin system (RAS) components and inflammatory mediators in diabetic rats. MAIN METHODS: Male Wistar rats (3 months old) were randomly assigned into four groups: non-trained (NT), trained (T), non-trained + diabetes (NTD) and trained +diabetes (TD). Diabetes was induced by streptozotocin (50 mg/kg, Sigma Chemical Co., St. Louis, MO, USA), before RT protocol. Trained rats performed RT protocol on a 110-cm ladder (8 ladder climbs, once/day, 5 days/week, 8 weeks), carrying a load corresponding to 50-80% of maximum carrying capacity. Blood glucose, albuminuria and urinary volume were measured. Renal levels of angiotensin peptides (angiotensin I, II and 1-7), inflammatory markers, and also the activities of angiotensin-converting enzyme (ACE) and ACE2 were determined. KEY FINDINGS: Blood glucose and urinary volume were elevated in diabetic animals, and RT decreased albuminuria, renal Ang I and Ang II levels in diabetic rats. RT shifted the balance of renal RAS toward ACE2/Ang 1-7 axis in TD group, and mitigated the high levels of interleukin (IL)-10, IL-1ß and cytokine-induced neutrophil chemoattractant 1 (CINC) in the context of diabetes. Strong positive correlations were found between albuminuria and Ang II, IL-10 and IL-1ß. On the other hand, intrarenal Ang 1-7 levels were negatively correlated with IL-10 and IL-1ß levels. SIGNIFICANCE: RT improved kidney function by modulating intrarenal RAS toward ACE2/Ang 1-7 axis and inflammatory cytokines. RT represents a reasonable strategy to improve the renal complications induced by diabetes, counteracting nephropathy-associated maladaptive responses.

Catecholamines production by kidney tissue and mesangial cell culture is differentially modulated by diabetes.

INTRODUCTION: According to the International Diabetes Federation, the number of people with diabetes mellitus may reach 700 million in 2045. Catecholamines are involved in the regulation of several kidney functions. This study investigates the effects of hyperglycemia on catecholamines' metabolism in kidney tissue from control, diabetic, and insulin-treated diabetic rats, both in vivo and in vitro. METHODS: Male Wistar-Hannover rats were randomized into: control, diabetic, and insulin-treated diabetic groups. Diabetes was induced by a single injection of streptozotocin, and diabetic treated group also received insulin. After 60 days, blood and kidney tissue from all groups were collected for catecholamines' quantification and mesangial cells culture. RESULTS: diabetic rats had lower body weight, hyperglycemia, and increase water intake and diuresis. Additionally, diabetes promoted a sharp decrease in creatinine clearance compared to control group. Regarding the whole kidney extracts, both diabetic groups (treated and non-treated) had significant reduction in norepinephrine concentration. In mesangial cell culture, catecholamines' concentration were lower in the culture medium than in the intracellular compartment for all groups. Norepinephrine, epinephrine, and dopamine medium levels were increased in the diabetic group. CONCLUSION: The major finding of the present study was that 8 weeks of diabetes induction altered the kidney catecholaminergic system in a very specific manner, once the production of catecholamines in the excised kidney tissue from diabetic rats was differentially modulated as compared with the production and secretion by cultured mesangial cells.

Super-enhancers maintain renin-expressing cell identity and memory to preserve multi-system homeostasis.

Renin cells are crucial for survival - they control fluid-electrolyte and blood pressure homeostasis, vascular development, regeneration, and oxygen delivery to tissues. During embryonic development, renin cells are progenitors for multiple cell types that retain the memory of the renin phenotype. When there is a threat to survival, those descendants are transformed and reenact the renin phenotype to restore homeostasis. We tested the hypothesis that the molecular memory of the renin phenotype resides in unique regions and states of these cells' chromatin. Using renin cells at various stages of stimulation, we identified regions in the genome where the chromatin is open for transcription, mapped histone modifications characteristic of active enhancers such as H3K27ac, and tracked deposition of transcriptional activators such as Med1, whose deletion results in ablation of renin expression and low blood pressure. Using the rank ordering of super-enhancers, epigenetic rewriting, and enhancer deletion analysis, we found that renin cells harbor a unique set of super-enhancers that determine their identity. The most prominent renin super-enhancer may act as a chromatin sensor of signals that convey the physiologic status of the organism, and is responsible for the transformation of renin cell descendants to the renin phenotype, a fundamental process to ensure homeostasis.

90-kDa N-domain angiotensin I-converting enzyme (ACE): possible marker for hypertension in a renal transplant model.

INTRODUCTION: Hypertension is nearly universal in kidney transplant and several factors are associated with post transplant hypertension, including immunosuppressive medications and genetic predisposition. OBJECTIVE: The aims were to evaluate the effects of spontaneously hypertensive rats (SHR) kidney transplantation in Wistar rats and the possible transference of 80/90-kDa N-domain ACE. METHODS: To do so, the data from Wistar recipients of kidney from SHR were compared to data from transplanted Wistar submitted to CsA treatment and, to Wistar Sham. RESULTS AND DISCUSSION: Despite the unaltered blood pressure observed at early stages, 80/90-kDa ACE was found expressed in the urine of rats 7 and 15 days after transplantation, which was intense when rats became hypertensive 30 days post-surgery. CONCLUSION: Our data show that this enzyme is associated with the development of hypertension, and this marker appears in the urine before any substantial blood pressure alteration.

90-kDa N-domain angiotensin I-converting enzyme (ACE): possible marker for hypertension in a renal transplant model / Enzima conversora de angiotensina I (ECA) N-domínio 90-kDa: possível marcador para hipertensão em modelo de transplante renal

Abstract Introduction: Hypertension is nearly universal in kidney transplant and several factors are associated with post transplant hypertension, including immunosuppressive medications and genetic predisposition. Objective: The aims were to evaluate the effects of spontaneously hypertensive rats (SHR) kidney transplantation in Wistar rats and the possible transference of 80/90-kDa N-domain ACE. Methods: To do so, the data from Wistar recipients of kidney from SHR were compared to data from transplanted Wistar submitted to CsA treatment and, to Wistar Sham. Results and Discussion: Despite the unaltered blood pressure observed at early stages, 80/90-kDa ACE was found expressed in the urine of rats 7 and 15 days after transplantation, which was intense when rats became hypertensive 30 days post-surgery. Conclusion: Our data show that this enzyme is associated with the development of hypertension, and this marker appears in the urine before any substantial blood pressure alteration.

Resumo Introdução: A hipertensão é altamente prevalente pós-transplante renal e vários fatores estão associados incluindo o tratamento com imunossupressores e a predisposição genética. Objetivo: Os objetivos foram avaliar os efeitos do transplante do rim de ratos espontaneamente hipertensos (SHR) em ratos Wistar, e a possível transferência da ECA N-domínio de 80/90-kDa para os tecidos dos receptores. Métodos: Para isso, os dados dos animais Wistar receptores dos rins de SHR foram comparados aos dados dos Wistar submetidos ao tratamento com CsA e Wistar Sham. Resultados e Discussão: Apesar da pressão arterial permanecer inalterada nos estágios iniciais pós-transplante renal, a expressão da ECA de 80/90-kDa foi identificada na urina de ratos 7 e 15 dias após o transplante, e de forma mais intensa aos 30 dias após a cirurgia, quando os animais tornaram-se hipertensos. Conclusão: Nossos dados mostram que ECA N-domínio está associada ao desenvolvimento da hipertensão, e que este marcador pode ser identificado na urina pós-transplante renal antes mesmo de qualquer alteração da pressão arterial.

Diabetic Nephropathy Induced by Increased Ace Gene Dosage Is Associated with High Renal Levels of Angiotensin (1-7) and Bradykinin.

Population studies have shown an association between diabetic nephropathy (DN) and insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene (ACE in humans, Ace in mice). The aim was to evaluate the modulation of Ace copies number and diabetes mellitus (DM) on renal RAS and correlate it with indicators of kidney function. Increased number of copies of the Ace gene, associated with DM, induces renal dysfunction. The susceptibility to the development of DN in 3 copies of animals is associated with an imbalance in activity of RAS enzymes leading to increased synthesis of Ang II and Ang-(1-7). Increased concentration of renal Ang-(1-7) appears to potentiate the deleterious effects triggered by Ang II on kidney structure and function. Results also show increased bradykinin concentration in 3 copies diabetic group. Taken together, results indicate that the deleterious effects described in 3 copies diabetic group are, at least in part, due to a combination of factors not usually described in the literature. Thus, the data presented here show up innovative and contribute to understanding the complex mechanisms involved in the development of DN, in order to optimize the treatment of patients with this complication.