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

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  Figure 1. Experimental design. CTL-Lean: sedentary lean rats; CTL-Obese: sedentary obese rats; Obese+AT: obese rats who underwent aerobic training without blocking of nitric oxide synthases; Obese+AT+L-NAME: obese rats who underwent aerobic training with blocking of nitric oxide synthases; L-NAME: N(ω)-nitro-L-arginine methyl ester; GTT: glucose tolerance test; ITT: insulin tolerance test; IT: incremental test; MLSS: maximal lactate steady state; BP: blood pressure; AT: aerobic training; eNOS: endothelial nitric oxide synthases; iNOS: inducible nitric oxide synthases. Male Zucker rats were selected at six weeks old. Rats belonging to the Obese+AT+L-NAME group received L-NAME 8 weeks prior to the beginning of the glycemic homeostasis tests and throughout the experimental design. All rats were analyzed GTT, ITT, IT, MLSS, and BP pre- and posttraining. All these analyses were performed with an interval of two days between them. After two days of the initial physical tests, the animals of trained groups were submitted to AT groups ran for 60 min at an intensity equivalent to 100% of MLSS, with 0% grade, 5 days/wk/8 wk. Afterward, 48 h of the last training session, each rat was isolated in a…

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  Figure 2. Swelling and production of species reactive to oxygen by the renal mitochondria. Data are presented as the mean ± SD. CTL-Lean: sedentary lean rats; CTL-Obese: sedentary obese rats; Obese+AT: obese rats who underwent aerobic training without blocking of nitric oxide synthases; Obese+AT+L-NAME: obese rats who underwent aerobic training with blocking of nitric oxide synthases. (a) Delta mitochondrial swelling. (b) The figure illustrates the fall in the absorbance of the renal mitochondria (swelling) against the insult with calcium chloride of the groups. (c) Production of species reactive to oxygen by the renal mitochondria. The one-way ANOVA followed by Tukey's post hoc test was adopted. The one-way ANOVA followed by Tukey's post hoc test was adopted. ∗p < 0.0001vs. CTL-Lean; †p < 0.0001vs. CTL-Obese; ‡p < 0.0001vs. AT.

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  Figure 3. Renal redox balance. Data are presented as the mean ± SD. CTL-Lean: sedentary lean rats; CTL-Obese: sedentary obese rats; Obese+AT: obese rats who underwent aerobic training without blocking of nitric oxide synthases; Obese+AT+L-NAME: obese rats who underwent aerobic training with blocking of nitric oxide synthases; TBARS: thiobarbituric acid-reactive substances; 3-NT: 3-nitrotyrosine; 8-OHdG: 8-hydroxydeoxyguanosine; SOD: superoxide dismutase; CAT: catalase; GSH/GSSG ratio: glutathione/glutathione disulfide ratio; TE: trolox equivalent. The one-way ANOVA followed by Tukey's post hoc test was adopted. ∗p < 0.0001vs. CTL-Lean; †p < 0.0001vs. CTL-Obese; ‡p < 0.0001vs. Obese+AT.

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  Figure 4. Renal klotho/FGF23 axis. Data are presented as the mean ± SD. CTL-Lean: sedentary lean rats; CTL-Obese: sedentary obese rats; Obese+AT: obese rats who underwent aerobic training without blocking of nitric oxide synthases; Obese+AT+L-NAME: obese rats who underwent aerobic training with blocking of nitric oxide synthases; FGF23: fibroblast growth factor 23. The one-way ANOVA followed by Tukey's post hoc test was adopted. ∗p < 0.05vs. CTL-Lean; †p < 0.0001vs. CTL-Obese; ‡p < 0.0001vs. Obese+AT.

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  Figure 5. Kidney vasoactive peptides. Data are presented as the mean ± SD. CTL-Lean: sedentary lean rats; CTL-Obese: sedentary obese rats; Obese+AT: obese rats who underwent aerobic training without blocking of nitric oxide synthases; Obese+AT+L-NAME: obese rats who underwent aerobic training with blocking of nitric oxide synthases; ANGII: angiotensin II; ANG-(1-7): angiotensin 1-7; ACE-1: angiotensin-converting enzyme 1; ACE-2: angiotensin-converting enzyme 2; AT1R: angiotensin II type-1 receptor; AT2R: angiotensin II type-2 receptor. The one-way ANOVA followed by Tukey's post hoc test was adopted. ∗p < 0.0001vs. CTL-Lean; †p < 0.0001vs. CTL-Obese; ‡p < 0.0001vs. Obese+AT.

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  Figure 6. Representative photomicrographs of the kidney. Hematoxylin-eosin staining. (a) CTL-Lean; (b) CTL-Obese; (c) Obese+AT; (d) Obese+AT+L-NAME. Black arrows indicate glomerulus, and white arrows indicate renal tubules. Magnification, 200x. ∗p < 0.0001vs. CTL-Lean; †p < 0.0001vs. CTL-Obese; ‡p < 0.0001vs. Obese+AT.

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  Figure 7. Mechanisms of vasoactive peptide integration. Angiotensinogen is transformed by renin in ANGI, which is cleaved by ACE-1 forming ANGII, interacting on AT1R increasing intraglomerular pressure, renal fibrosis, mesangial proliferation, proteinuria, vasopressin release, decreased sodium excretion, and activation of the NOX complex, which induces ROS, inflammation, and insulin resistance, which are common complications of cardiometabolic diseases [58, 71, 81]. However, AT decreases ACE-1 and AT1R in the kidney, which was partly responsible for renoprotection. In addition, AT increased ACE-2, which converts ANGII to ANG-(1-7) that interact with MasR and/or ANGII acting on AT2R to promote a vasodilatory, antifibrotic, antioxidant, and anti-inflammatory effect, as well as an increase in sodium excretion and maintenance of intrarenal hemodynamics. C-EX: chronic exercise training; ACE-1: angiotensin-converting enzyme 1; ACE-2: angiotensin-converting enzyme 2; AT1R: angiotensin II type-1 receptor; AT2R: angiotensin II type-2 receptor; MasR: receptor MasR; ROS: reactive oxygen species; ADMA: asymmetric dimethylarginine; NO: nitric oxide.