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Renal response to short- and long-term exercise in very-long-chain acyl-CoA dehydrogenase-deficient (VLCAD − / − ) mice

View Article: PubMed Central

ABSTRACT

Background: Deficiency of very long-chain acyl-CoA dehydrogenase (VLCAD) is the most common disorder of mitochondrial β-oxidation of long-chain fatty acids. In order to maintain glucose homeostasis, the kidney and liver as the main gluconeogenic organs play an important role under conditions of impaired fatty acid oxidation. However, little is known about how a defective fatty acid oxidation machinery affects renal metabolism and function as well as renal energy supply especially during catabolic situations.

Methods: In this study, we analyzed VLCAD−/− mice under different metabolic conditions such as after moderate (1 h) and intensive long-term (1 h twice per day over 2 weeks) physical exercise and after 24 h of fasting. We measured the oxidation rate of palmitoyl-CoA (C16-CoA) as well as the expression of genes involved in lipogenesis and renal failure. Oxidative stress was assessed by the function of antioxidant enzymes. Moreover, we quantified the content of glycogen and long-chain acylcarnitines in the kidney.

Results: We observed a significant depletion in renal glycogen with a concomitant reduction in long-chain acylcarnitines, suggesting a substrate switch for energy production and an optimal compensation of impaired fatty acid oxidation in the kidney. In fact, the mutants did not show any signs of oxidative stress or renal failure under catabolic conditions.

Conclusions: Our data demonstrate that despite Acadvl ablation, the kidney of VLCAD−/− mice fully compensates for impaired fatty acid oxidation by enhanced glycogen utilization and preserves renal energy metabolism and function.

No MeSH data available.


Related in: MedlinePlus

Expression of genes upregulated during renal failure. (A)Ngal, lipocalin; (B)KIM1, kidney injury molecule 1; (C)Ho1, heme oxygenase 1. White and black bars represent WT and VLCAD−/− mice, respectively. Values are represented as mean ± SEM (n = 5 to 6). Asterisk indicates significant differences between WT and VLCAD−/− mice within an experimental set. Number sign indicates significant differences between WT or VLCAD−/− mice under different stress conditions as compared to resting mice. Asterisk and number sign denote that values were considered significant if p < 0.05 (two-way ANOVA with Bonferroni correction and Student's t test).
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Fig4: Expression of genes upregulated during renal failure. (A)Ngal, lipocalin; (B)KIM1, kidney injury molecule 1; (C)Ho1, heme oxygenase 1. White and black bars represent WT and VLCAD−/− mice, respectively. Values are represented as mean ± SEM (n = 5 to 6). Asterisk indicates significant differences between WT and VLCAD−/− mice within an experimental set. Number sign indicates significant differences between WT or VLCAD−/− mice under different stress conditions as compared to resting mice. Asterisk and number sign denote that values were considered significant if p < 0.05 (two-way ANOVA with Bonferroni correction and Student's t test).

Mentions: To appoint the development of oxidative stress due to catabolism as occur in VLCAD−/− mice [11], we measured the specific activity of NADPH:quinone oxidoreductase, GPX, and catalase, which are antioxidant enzymes neutralizing oxidative stress of cytosolic, mitochondrial, and peroxisomal origin, respectively. However, neither the activity of NADPH:quinone oxidoreductase nor of catalase was affected by fasting or exercise, (Figure 3A,B), with the exception of GPX activity, which was significantly reduced in the VLCAD−/− mice as compared to WT after the exercise of about 2 weeks (8.51 ± 0.45 vs. 16.97 ± 3.88 U/mg; Figure 3C). These data are in line with the reduced C16-CoA oxidation rate. Moreover, the expression of genes massively upregulated immediately prior to kidney failure, namely, Ngal, KIM1, and Ho1, was unaffected under all applied stress conditions (Figure 4A,B,C).Figure 3


Renal response to short- and long-term exercise in very-long-chain acyl-CoA dehydrogenase-deficient (VLCAD − / − ) mice
Expression of genes upregulated during renal failure. (A)Ngal, lipocalin; (B)KIM1, kidney injury molecule 1; (C)Ho1, heme oxygenase 1. White and black bars represent WT and VLCAD−/− mice, respectively. Values are represented as mean ± SEM (n = 5 to 6). Asterisk indicates significant differences between WT and VLCAD−/− mice within an experimental set. Number sign indicates significant differences between WT or VLCAD−/− mice under different stress conditions as compared to resting mice. Asterisk and number sign denote that values were considered significant if p < 0.05 (two-way ANOVA with Bonferroni correction and Student's t test).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
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getmorefigures.php?uid=PMC4530567&req=5

Fig4: Expression of genes upregulated during renal failure. (A)Ngal, lipocalin; (B)KIM1, kidney injury molecule 1; (C)Ho1, heme oxygenase 1. White and black bars represent WT and VLCAD−/− mice, respectively. Values are represented as mean ± SEM (n = 5 to 6). Asterisk indicates significant differences between WT and VLCAD−/− mice within an experimental set. Number sign indicates significant differences between WT or VLCAD−/− mice under different stress conditions as compared to resting mice. Asterisk and number sign denote that values were considered significant if p < 0.05 (two-way ANOVA with Bonferroni correction and Student's t test).
Mentions: To appoint the development of oxidative stress due to catabolism as occur in VLCAD−/− mice [11], we measured the specific activity of NADPH:quinone oxidoreductase, GPX, and catalase, which are antioxidant enzymes neutralizing oxidative stress of cytosolic, mitochondrial, and peroxisomal origin, respectively. However, neither the activity of NADPH:quinone oxidoreductase nor of catalase was affected by fasting or exercise, (Figure 3A,B), with the exception of GPX activity, which was significantly reduced in the VLCAD−/− mice as compared to WT after the exercise of about 2 weeks (8.51 ± 0.45 vs. 16.97 ± 3.88 U/mg; Figure 3C). These data are in line with the reduced C16-CoA oxidation rate. Moreover, the expression of genes massively upregulated immediately prior to kidney failure, namely, Ngal, KIM1, and Ho1, was unaffected under all applied stress conditions (Figure 4A,B,C).Figure 3

View Article: PubMed Central

ABSTRACT

Background: Deficiency of very long-chain acyl-CoA dehydrogenase (VLCAD) is the most common disorder of mitochondrial &beta;-oxidation of long-chain fatty acids. In order to maintain glucose homeostasis, the kidney and liver as the main gluconeogenic organs play an important role under conditions of impaired fatty acid oxidation. However, little is known about how a defective fatty acid oxidation machinery affects renal metabolism and function as well as renal energy supply especially during catabolic situations.

Methods: In this study, we analyzed VLCAD&minus;/&minus; mice under different metabolic conditions such as after moderate (1&nbsp;h) and intensive long-term (1&nbsp;h twice per day over 2&nbsp;weeks) physical exercise and after 24&nbsp;h of fasting. We measured the oxidation rate of palmitoyl-CoA (C16-CoA) as well as the expression of genes involved in lipogenesis and renal failure. Oxidative stress was assessed by the function of antioxidant enzymes. Moreover, we quantified the content of glycogen and long-chain acylcarnitines in the kidney.

Results: We observed a significant depletion in renal glycogen with a concomitant reduction in long-chain acylcarnitines, suggesting a substrate switch for energy production and an optimal compensation of impaired fatty acid oxidation in the kidney. In fact, the mutants did not show any signs of oxidative stress or renal failure under catabolic conditions.

Conclusions: Our data demonstrate that despite Acadvl ablation, the kidney of VLCAD&minus;/&minus; mice fully compensates for impaired fatty acid oxidation by enhanced glycogen utilization and preserves renal energy metabolism and function.

No MeSH data available.


Related in: MedlinePlus