Influence of Angiotensin Converting Enzyme I/D Polymorphism on Hemodynamic and Antioxidant Response to Long-Term Intradialytic Resistance Training in Patients With Chronic Kidney Disease: A Randomized Controlled Trial.

ABSTRACT: Corrêa, HdL, Deus, LA, Neves, RVP, Reis, AL, de Freitas, GS, de Araújo, TB, da Silva Barbosa, JM, Prestes, J, Simões, HG, Amorim, CE, dos Santos, MAP, Haro, A, de Melo, GF, Gadelha, AB, Neto, LS, and Rosa, TdS. Influence of angiotensin converting enzyme I/D polymorphism on hemodynamic and antioxidant response to long-term intradialytic resistance training in patients with chronic kidney disease: a randomized controlled trial. J Strength Cond Res 35(10): 2902-2909, 2021-The aim of the study was to verify the influence of Angiotensin-converting enzyme (ACE) I/D genotype on blood pressure, muscle mass, and redox balance response to long-term resistance training (RT) in end-stage renal disease patients. Three hundred and twenty subjects were randomized into 4 groups: II + ID control (II + ID CTL, n = 80), II + ID RT (II + ID RT, n = 79), DD control (DD CTL n = 83), and DD RT (DD RT, n = 78). The RT lasted 24 weeks with a frequency of 3 times per week, on alternative days. Each section consisted of 3 sets of 8-12 repetitions in 11 exercises, with training loads at 6 point (somewhat hard) to 8 point (hard) based on OMNI-RES scale and was prescribed during dialysis (intradialytic). Statistical significance was accepted with p < 0.05. The most relevant benefits in blood pressure were found for DD homozygotes (p < 0.0001), whereas allele I carriers displayed a higher increase in muscle mass (p < 0.0001). Hemodialysis clinics that already use RT for their patients could include the genotyping of ACE to identify the predisposal of the patients to respond to RT and to counteract kidney disease-related comorbidities.

Exercise and caloric restriction alter the immune system of mice submitted to a high-fat diet.

As the size of adipocytes increases during obesity, the establishment of resident immune cells in adipose tissue becomes an important source of proinflammatory mediators. Exercise and caloric restriction are two important, nonpharmacological tools against body mass increase. To date, their effects on the immune cells of adipose tissue in obese organisms, specifically when a high-fat diet is consumed, have been poorly investigated. Thus, after consuming a high-fat diet, mice were submitted to chronic swimming training or a 30% caloric restriction in order to investigate the effects of both interventions on resident immune cells in adipose tissue. These strategies were able to reduce body mass and resulted in changes in the number of resident immune cells in the adipose tissue and levels of cytokines/chemokines in serum. While exercise increased the number of NK cells in adipose tissue and serum levels of IL-6 and RANTES, caloric restriction increased the CD4+/CD8+ cell ratio and MCP-1 levels. Together, these data demonstrated that exercise and caloric restriction modulate resident immune cells in adipose tissues differently in spite of an equivalent body weight reduction. Additionally, the results also reinforce the idea that a combination of both strategies is better than either individually for combating obesity.

Bradykinin inhibits hepatic gluconeogenesis in obese mice.

The kallikrein-kinin system (KKS) has been previously linked to glucose homeostasis. In isolated muscle or fat cells, acute bradykinin (BK) stimulation was shown to improve insulin action and increase glucose uptake by promoting glucose transporter 4 translocation to plasma membrane. However, the role for BK in the pathophysiology of obesity and type 2 diabetes remains largely unknown. To address this, we generated genetically obese mice (ob/ob) lacking the BK B2 receptor (obB2KO). Despite similar body weight or fat accumulation, obB2KO mice showed increased fasting glycemia (162.3 ± 28.2 mg/dl vs 85.3 ± 13.3 mg/dl), hyperinsulinemia (7.71 ± 1.75 ng/ml vs 4.09 ± 0.51 ng/ml) and impaired glucose tolerance when compared with ob/ob control mice (obWT), indicating insulin resistance and impaired glucose homeostasis. This was corroborated by increased glucose production in response to a pyruvate challenge. Increased gluconeogenesis was accompanied by increased hepatic mRNA expression of forkhead box protein O1 (FoxO1, four-fold), peroxisome proliferator-activated receptor gamma co-activator 1-alpha (seven-fold), phosphoenolpyruvate carboxykinase (PEPCK, three-fold) and glucose-6-phosphatase (eight-fold). FoxO1 nuclear exclusion was also impaired, as the obB2KO mice showed increased levels of this transcription factor in the nucleus fraction of liver homogenates during random feeding. Intraportal injection of BK in lean mice was able to decrease the hepatic mRNA expression of FoxO1 and PEPCK. In conclusion, BK modulates glucose homeostasis by affecting hepatic glucose production in obWT. These results point to a protective role of the KKS in the pathophysiology of type 2 diabetes mellitus.

Chronic conventional resistance exercise reduces blood pressure in stage 1 hypertensive men.

To investigate the antihypertensive effects of conventional resistance exercise (RE) on the blood pressure (BP) of hypertensive subjects, 15 middle-aged (46 ± 3 years) hypertensive volunteers, deprived of antihypertensive medication (reaching 153 ± 6/93 ± 2 mm Hg systolic/diastolic BP after a 6-week medication washout period) were submitted to a 12-week conventional RE training program (3 sets of 12 repetitions at 60% 1 repetition maximum, 3 times a week on nonconsecutive days). Blood pressure was measured in all phases of the study (washout, training, detraining). Additionally, the plasma levels of several vasodilators or vasoconstrictors that potentially could be involved with the effects of RE on BP were evaluated pre- and posttraining. Conventional RE significantly reduced systolic, diastolic, and mean BP, respectively, by an average of 16 (p < 0.001), 12 (p < 0.01), and 13 mm Hg (p < 0.01) to prehypertensive values. There were no significant changes of vasoactive factors from the kallikrein-kinin or renin-angiotensin systems. After the RE training program, the BP values remained stable during a 4-week detraining period. Taken together, this study shows for the first time that conventional moderate-intensity RE alone is able to reduce the BP of stage 1 hypertensive subjects free of antihypertensive medication. Moreover, the benefits of BP reduction achieved with RE training remained unchanged for up to 4 weeks without exercise.

Metabolic and hormonal responses to chronic blood-flow restricted resistance training in chronic kidney disease: a randomized trial.

Maintenance of glycemic and lipemic homeostasis can limit the progression of diabetic kidney disease. Resistance training (RT) is effective in controlling glycemia and lipemia in kidney disease; however, the effect of RT with blood flow restriction (RT+BFR) on these metabolic factors has not been investigated. We aimed to verify if chronic (6 months) RT and RT+BFR performed by patients with stage-2 chronic kidney disease (CKD) improves their glycemic homeostasis and immunometabolic profiles. Patients with CKD under conservative treatment (n = 105 (33 females)) from both sexes were randomized into control (n = 35 (11 females); age 57.6 ± 5.2 years), RT (n = 35 (12 females); age 58.0 ± 6.2 years), and RT+BFR (n = 35 (10 females); 58.0 ± 6.4 years) groups. Chronic RT or RT+BFR (6 months) was performed 3 times per week on non-consecutive days with training loading adjusted every 2 months, RT 50%-60%-70% of 1RM, and RT+BFR 30%-40%+50% of 1RM and fixed repetition number. Renal function was estimated with the glomerular filtration rate and serum albumin level. Metabolic, hormonal, and inflammatory assessments were analyzed from blood samples. Six months of RT and RT+BFR were similarly effective in improving glucose homeostasis and hormone mediators of glucose uptake (e.g., irisin, adiponectin, and sirtuin-1), decreasing pro-inflammatory and fibrotic proteins, and attenuating the progression of estimated glomerular filtration rate. Thus, RT+BFR can be considered an additional exercise modality to be included in the treatment of patients with stage 2 chronic kidney disease. Trial registration number: U1111-1237-8231. URL: http://www.ensaiosclinicos.gov.br/rg/RBR-3gpg5w/, no. RBR-3gpg5w. Novelty: Glycemic regulation induced by resistance training prevents the progression of CKD. Chronic RT and RT+BFR promote similar changes in glycemic regulation. RT and RT+BFR can be considered as non-pharmacological tools for the treatment of CKD.

Blood Flow Restriction Training Blunts Chronic Kidney Disease Progression in Humans.

PURPOSE: This study aimed to verify the effect of 6 months of periodized resistance training (RT) with and without blood flow restriction (BFR) in patients with stage 2 chronic kidney disease (CKD) on glomerular filtration rate (GFR), uremic parameters, cytokines, and klotho-fibroblast growth factor 23 (FGF23) axis. METHODS: A total of 105 subjects were randomized in three groups of 35 each: control (CTL), RT, and RT + BFR. A first visit was required for an anamnesis to evaluate the number of medications and anthropometric measurements (body weight, height, and body mass index). Muscle strength (one-repetition maximum) was assessed. Venous blood samples were collected at baseline and after 6 months of training in all patients for the analysis of markers of renal function and integrity, as well as for the determination of the inflammatory profile. Statistical significances were adopted with P < 0.05. RESULTS: Both training therapies attenuated the decline of GFR (P < 0.05). The majority of CTL patients declined to stage 3 CKD (88.5%), whereas fewer incidents were noted with RT (25.7%) and RT + BFR (17.1%). Improved uremic parameters as well as inflammation (IL-6, IL-10, IL-15, IL-17a, IL-18, and TNF-α) and klotho-FGF23 axis in RT and RT + BFR (P < 0.05) were observed. Monocyte chemoattractant protein 1 was not changed (P > 0.05) but presented a large effect size (Cohen's d), demonstrating a propensity for improvement. CONCLUSION: Six months of periodized RT with and without BFR in patients with stage 2 CKD attenuated the progression of the disease by maintaining GFR, improving uremic parameters, cytokine profile regulation, and klotho-FGF23 axis.

Low-load resistance training with blood flow restriction prevent renal function decline: The role of the redox balance, angiotensin 1-7 and vasopressin✰,✰✰.

AIMS: We sought to investigate the effect of resistance training (RT) and low-load RT with moderate blood flow restriction (RT+BFR) on blood pressure, exercise pressor response, redox balance and vasoactive peptides, body composition and muscle strength in patients with stage two of chronic kidney disease (CKD). METHODS: We conducted a 6-month randomized controlled exercise intervention in 90 male and female hypertensive CKD patients (58±9 years with estimated glomerular filtration rate (eGFR; of 66.1 ± 1.2 mL/kg/1.73m2). Participants were randomized to one of three groups (n = 30/group); control group (CTL), RT, and RT+BFR. RT and RT+BFR performed three weekly training sessions using similar periodization for six months (two-month mesocycles), but of different intensities. RESULTS: There was similarly effects between RT and RT+BFR in reducing systolic and diastolic blood pressure during daytime and 24hour period (RT: 10.4%; RT+BFR: 10.3% of decrease), fat mass, F2-isoprostanes, asymmetric dimethylarginine (ADMA) and vasopressin (p<0.05 pre-vs post). Also promoted the increase of angiotensin 1-7, nitric oxide (NO), catalase, Trolox equivalent and muscle strength (p<0.05). Both training models attenuated the decline of estimated glomerular filtration rate (p<0.0001 vs CTL). However, only RT+BFR was associated with lower discomfort during exercise (p<0.0001 pre-vs post). Statistical significance was considered with p < 0.05. CONCLUSION: These findings suggest low-load RT+BFR as a promising non-pharmacological strategy to control blood pressure, oxidative stress, vasoactive peptides, and consequently, attenuate the decrease of the eGFR.

Renoprotection Induced by Aerobic Training Is Dependent on Nitric Oxide Bioavailability in Obese Zucker Rats.

Aerobic training (AT) promotes several health benefits that may attenuate the progression of obesity associated diabetes. Since AT is an important nitric oxide (NO-) inducer mediating kidney-healthy phenotype, the present study is aimed at investigating the effects of AT on metabolic parameters, morphological, redox balance, inflammatory profile, and vasoactive peptides in the kidney of obese-diabetic Zucker rats receiving L-NAME (N(omega)-nitro-L-arginine methyl ester). Forty male Zucker rats (6 wk old) were assigned into four groups (n = 10, each): sedentary lean rats (CTL-Lean), sedentary obese rats (CTL-Obese), AT trained obese rats without blocking nitric oxide synthase (NOS) (Obese+AT), and obese-trained with NOS block (Obese+AT+L-NAME). AT groups ran 60 min in the maximal lactate steady state (MLSS), five days/wk/8 wk. Obese+AT rats improved glycemic homeostasis, SBP, aerobic capacity, renal mitochondria integrity, redox balance, inflammatory profile (e.g., TNF-α, CRP, IL-10, IL-4, and IL-17a), and molecules related to renal NO- metabolism (klotho/FGF23 axis, vasoactive peptides, renal histology, and reduced proteinuria). However, none of these positive outcomes were observed in CTL-Obese and Obese+AT+L-NAME (p < 0.0001) groups. Although Obese+AT+L-NAME lowered BP (compared with CTL-Obese; p < 0.0001), renal damage was observed after AT intervention. Furthermore, AT training under conditions of low NO- concentration increased signaling pathways associated with ACE-2/ANG1-7/MASr. We conclude that AT represents an important nonpharmacological intervention to improve kidney function in obese Zucker rats. However, these renal and metabolic benefits promoted by AT are dependent on NO- bioavailability and its underlying regulatory mechanisms.

Resistance training improves sleep quality, redox balance and inflammatory profile in maintenance hemodialysis patients: a randomized controlled trial.

Patients in maintenance hemodialisys (HD) present sleep disorders, increased inflammation, unbalanced redox profiles, and elevated biomarkers representing endothelial dysfunction. Resistance training (RT) has shown to mitigate the loss of muscle mass, strength, improve inflammatory profiles, and endothelial function while decreasing oxidative stress for those in HD. However, the relation between those factors and sleep quality are inadequately described. The aim of this study was to verify the effects of 3 months of RT on sleep quality, redox balance, nitric oxide (NO) bioavailability, inflammation profile, and asymmetric dimethylarginine (ADMA) in patients undergoing HD. Our primary goal was to describe the role of RT on sleep quality. Our secondary goal was to evaluate the effect of RT on NO, metabolism markers, and inflammatory and redox profiles as potential mechanisms to explain RT-induced sleep quality changes. Fifty-five men undergoing maintenance hemodialysis were randomized into either a control (CTL, n = 25) and RT group (RTG; n = 30). Participants in the RT group demonstrated an improvement in sleep pattern, redox, inflammatory profiles, and biomarkers of endothelial function (NO2- and ADMA). This group also increased muscle strength (total workload in RT exercises of upper and lower limbs). These findings support that RT may improve the clinical status of HD patients by improving their sleep quality, oxidative and inflammatory parameters.

l-Arginine supplementation blunts resistance exercise improvement in rats with chronic kidney disease.

Chronic kidney disease (CKD) patients present L-arginine (L-arg) deficiency and L-arg supplementation has been used as a treatment. In addition, sarcopenia is another common problem in CKD population, resistance training (RT) is one of the conservative strategies developed to prevent CKD progression, and however there are no evidences of a combination of these two strategies to treat CKD outcomes. The aim of this study was to evaluate the effects of oral L-arg supplementation combined with RT in an experimental model of CKD. Twenty-five Munich-Wistar male rats, 8-week-old were divided in 5 groups: Sham (sedentary control), Nx (CKD sedentary), Nx L-arg (CKD sedentary supplemented with 2% of L-arg), Nx RT (CKD exercised) Nx RT + L-arg (CKD exercised and supplemented with 2% of L-arg). CKD model was obtained by a subtotal 5/6 nephrectomy. RT was performed on a ladder climbing, three weekly sessions on non-consecutive days, with an intensity of 70% maximum carrying capacity. They were submitted to RT and/or L-arg supplementation for 10 weeks. There was a significant improvement in muscle strength, renal function, anti-inflammatory cytokines, arginase metabolism and renal fibrosis after RT. However, the combination of RT and L-arg impaired all the improvements promoted by RT alone. The L-arg supplementation alone did not impair renal fibrosis and renal function. In conclusion, RT improved inflammatory balance, muscle strength, renal function and consequently decreased renal fibrosis. Nevertheless, the association with L-arg supplementation prevented all these effects promoted by RT.

Acute metabolic responses following different resistance exercise protocols.

Resistance exercise (RE) can be an excellent modality for glycemic control. Studies have demonstrated that a single RE session can reduce glycemia in subjects with or without diabetes. Little is known about the dose-response effect of RE on glycemic control. This study aimed to investigate the acute metabolic responses after different RE protocols. Eighty-nine males were separated into six groups that completed RE protocols: 2 sets of 18 repetitions (2 × 18 at 50% of 1-repetition maximum (1RM); n = 19); 3 sets of 12 repetitions (3 × 12 at 70% of 1RM; n = 14); 4 sets of 9 repetitions (4 × 9 at 80% of 1RM; n = 13); 6 sets of 6 repetitions (6 × 6 at 90% of 1RM; n = 19); circuit (2 × 18 at 50% of 1RM; n = 12); and a control session (n = 12). The exercise sequence consisted of 8 exercises. An oral glucose tolerance test was conducted with metabolic measurements immediately after each RE protocol and every 15 min until 120 min of recovery. All groups exhibited significantly lower values (p < 0.05) in the glucose area under the curve (AUC) when compared with control over a 120 min monitoring period. The 6 × 6 group showed a significantly lower glucose AUC versus the 3 × 12 and 4 × 9 groups (p = 0.004; p = 0.001, respectively). As for blood lactate, the control and 6 × 6 groups exhibited lower AUC values versus all other groups (p < 0.05), and AUC for glucose and lactate concentration showed a negative and significant correlation (r = -0.46; p < 0.0001). It appears that a combination of 9-12 repetitions per set and 3-4 sets per muscle group might be optimal for acute postprandial glucose control.

Deletion of Kinin B2 Receptor Alters Muscle Metabolism and Exercise Performance.

Metabolic syndrome is a cluster of metabolic risk factors such as obesity, diabetes and cardiovascular diseases. Mitochondria is the main site of ATP production and its dysfunction leads to decreased oxidative phosphorylation, resulting in lipid accumulation and insulin resistance. Our group has demonstrated that kinins can modulate glucose and lipid metabolism as well as skeletal muscle mass. By using B2 receptor knockout mice (B2R-/-) we investigated whether kinin action affects weight gain and physical performance of the animals. Our results show that B2R-/- mice are resistant to high fat diet-induced obesity, have higher glucose tolerance as well as increased mitochondrial mass. These features are accompanied by higher energy expenditure and a lower feed efficiency associated with an increase in the proportion of type I fibers and intermediary fibers characterized by higher mitochondrial content and increased expression of genes related to oxidative metabolism. Additionally, the increased percentage of oxidative skeletal muscle fibers and mitochondrial apparatus in B2R-/- mice is coupled with a higher aerobic exercise performance. Taken together, our data give support to the involvement of kinins in skeletal muscle fiber type distribution and muscle metabolism, which ultimately protects against fat-induced obesity and improves aerobic exercise performance.

Altered glucose homeostasis and hepatic function in obese mice deficient for both kinin receptor genes.

The Kallikrein-Kinin System (KKS) has been implicated in several aspects of metabolism, including the regulation of glucose homeostasis and adiposity. Kinins and des-Arg-kinins are the major effectors of this system and promote their effects by binding to two different receptors, the kinin B2 and B1 receptors, respectively. To understand the influence of the KKS on the pathophysiology of obesity and type 2 diabetes (T2DM), we generated an animal model deficient for both kinin receptor genes and leptin (obB1B2KO). Six-month-old obB1B2KO mice showed increased blood glucose levels. Isolated islets of the transgenic animals were more responsive to glucose stimulation releasing greater amounts of insulin, mainly in 3-month-old mice, which was corroborated by elevated serum C-peptide concentrations. Furthermore, they presented hepatomegaly, pronounced steatosis, and increased levels of circulating transaminases. This mouse also demonstrated exacerbated gluconeogenesis during the pyruvate challenge test. The hepatic abnormalities were accompanied by changes in the gene expression of factors linked to glucose and lipid metabolisms in the liver. Thus, we conclude that kinin receptors are important for modulation of insulin secretion and for the preservation of normal glucose levels and hepatic functions in obese mice, suggesting a protective role of the KKS regarding complications associated with obesity and T2DM.