Effects of telmisartan and pioglitazone on high fructose induced metabolic syndrome in rats

Shahataa, Mary Girgis; Mostafa‐Hedeab, Gomaa; Ali, E. Fouaad; Mahdi, Emad A.; Mahmoud, Faten Shafik

doi:10.1139/cjpp-2016-0090

Cited by 16 publications

(16 citation statements)

References 71 publications

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“…In a related issue, treatment of diabetic patients with thiazolidinediones has also been reported to result in weight gain [16], but this may also be an effect specific to humans. Similar to our results with RGZ, in numerous animal models with HFD alone or HFD in combination with other diets, the thiazolidinidones did not induce additional weight gain in rats with metabolic syndrome [45–48]. …”

Section: Discussionsupporting

confidence: 89%

Regulatory landscape of AGE-RAGE-oxidative stress axis and its modulation by PPARγ activation in high fructose diet-induced metabolic syndrome

Cannizzaro

Rossoni

Savi³

et al. 2017

Nutr Metab (Lond)

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BackgroundThe AGE-RAGE-oxidative stress (AROS) axis is involved in the onset and progression of metabolic syndrome induced by a high-fructose diet (HFD). PPARγ activation is known to modulate metabolic syndrome; however a systems-level investigation looking at the protective effects of PPARγ activation as related to the AROS axis has not been performed.The aim of this work is to simultaneously characterize multiple molecular parameters within the AROS axis, using samples taken from different body fluids and tissues of a rat model of HFD-induced metabolic syndrome, in the presence or absence of a PPARγ agonist, Rosiglitazone (RGZ).MethodsRats were fed with 60% HFD for the first half of the treatment duration (21 days) then continued with either HFD alone or HFD plus RGZ for the second half.ResultsRats receiving HFD alone showed metabolic syndrome manifestations including hypertension, dyslipidemia, increased glucose levels and insulin resistance, as well as abnormal kidney and inflammatory parameters. Systolic blood pressure, plasma triglyceride and glucose levels, plasma creatinine, and albuminuria were significantly improved in the presence of RGZ. The following molecular parameters of the AROS axis were significantly upregulated in our rat model: carboxymethyl lysine (CML) in urine and liver; carboxyethyl lysine (CEL) in urine; advanced glycation end products (AGEs) in plasma; receptor for advanced glycation end products (RAGE) in liver and kidney; advanced oxidation protein products (AOPP) in plasma; and 4-hydroxynonenal (HNE) in plasma, liver, and kidney. Conversely, with RGZ administration, the upregulation of AOPP and AGEs in plasma, CML and CEL in urine, RAGE in liver as well as HNE in plasma and liver was significantly counteracted/prevented.ConclusionsOur data demonstrate (i) the systems-level regulatory landscape of HFD-induced metabolic syndrome involving multiple molecular parameters, including HNE, AGEs and their receptor RAGE, and (ii) attenuation of metabolic syndrome by PPARγ modulation.Electronic supplementary materialThe online version of this article (doi:10.1186/s12986-016-0149-z) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 89%

Regulatory landscape of AGE-RAGE-oxidative stress axis and its modulation by PPARγ activation in high fructose diet-induced metabolic syndrome

Cannizzaro

Rossoni

Savi³

et al. 2017

Nutr Metab (Lond)

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“…A telmisartan dose of 5 mg/kg/day is usually well tolerated (Rabie et al 2015, Shahataa et al 2016. Toxicity studies in Wistar rats demonstrated that even a telmisartan dose of 150 mg/kg/day is not associated with any adverse effects (Sengupta et al 2016).…”

Section: Discussionmentioning

confidence: 99%

Acute Toxic Effects of Telmisartan in Spontaneously Hypertensive Rats Fed a High Fructose Diet

Šilhavý

Mlejnek²,

Šimáková³

et al. 2018

Physiol Res

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Telmisartan is an angiotensin receptor blocker (ARB) and a selective peroxisome proliferator activated receptor gamma (PPARG) modulator. Recently, we tested metabolic effects of telmisartan (5 mg/kg body weight) in spontaneously hypertensive rats (SHR) fed a diet containing 60 % fructose, a widely used model of the metabolic syndrome. Surprisingly, we observed acute toxic effects of telmisartan. Rats lost body weight rapidly and died within 2 to 3 weeks due to bleeding into the upper gastrointestinal tract. SHR fed a high fructose diet and treated with telmisartan exhibited rapid decrease in blood pressure when compared to the SHR fed a high fructose diet and treated with valsartan. Concentrations of both unconjugated telmisartan and telmisartan glucuronide in the liver of SHR rats fed a high fructose diet were approximately 4 fold higher when compared to Brown Norway (BN) rats fed the same diet. Plasma concentrations of unconjugated telmisartan in the SHR were about 5 fold higher when compared to BN rats while plasma levels of telmisartan glucuronide were similar between the strains. Testing of other rat strains, diets, and the ARB valsartan showed that toxic effects of telmisartan in combination with high fructose diet are specific for the SHR. These results are consistent with the possibility that in some circumstances, SHR are predisposed to telmisartan toxicity possibly because of a genetically determined disturbance in telmisartan metabolism. * denotes P<0.05 statistically significant difference of one-way ANOVA; # denotes statistical significance P<0.05 of multiple comparisons versus SHR (FD + telmisartan) control group by Holm-Sidak method.

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“…Sub-nanomolar Ang II concentrations stimulate both Na + entry [ 30 ] via NHEs and exit via Na + /K + -ATPase [ 31 ]. Interfering with the effects of Ang II blunts the increase in blood pressure in fructose-fed rats [ 32 , 33 , 34 , 35 , 36 , 37 ]. Furthermore, we reported that dietary fructose in the absence of a high-salt diet enhances the sensitivity of proximal nephron Na + transport to the stimulatory effect of Ang II [ 38 ].…”

Section: Introductionmentioning

confidence: 99%

Dietary Fructose Increases the Sensitivity of Proximal Tubules to Angiotensin II in Rats Fed High-Salt Diets

et al. 2018

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Dietary fructose causes salt-sensitive hypertension. Proximal tubules (PTs) reabsorb 70% of the filtered NaCl. Angiotensin II (Ang II), atrial natriuretic peptide (ANP) and norepinephrine (NE) regulate this process. Although Ang II signaling blockade ameliorates fructose-induced salt-sensitive hypertension, basal PT Na+ reabsorption and its sensitivity to the aforementioned factors have not been studied in this model. We hypothesized consuming fructose with a high-salt diet selectively enhances the sensitivity of PT transport to Ang II. We investigated the effects of Ang II, ANP and NE on PT Na reabsorption in rats fed a high-salt diet drinking tap water (HS) or 20% fructose (HS-FRU). Oxygen consumption (QO2) was used as a measure of all ATP-dependent transport processes. Na+/K+-ATPase and Na+/H+-exchange (NHE) activities were studied because they represent primary apical and basolateral transporters in this segment. The effect of 10−12 mol/L Ang II in QO2 by PTs from HS-FRU was larger than HS (p < 0.02; n = 7). In PTs from HS-FRU 10−12 mol/L Ang II stimulated NHE activity by 2.6 ± 0.7 arbitrary fluorescence units/s (p < 0.01; n = 5) but not in those from HS. The stimulatory effect of Ang II on PT Na+/K+-ATPase activity was not affected by HS-FRU. Responses of QO2 and NHE activity to ANP did not differ between groups. The response of QO2 to NE was unaltered by HS-FRU. We concluded that the sensitivity of PT Na+ reabsorption specifically to Ang II is enhanced by HS-FRU. This maintains high rates of transport even in the presence of low concentrations of the peptide, and likely contributes to the hypertension.

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Effects of telmisartan and pioglitazone on high fructose induced metabolic syndrome in rats

Cited by 16 publications

References 71 publications

Regulatory landscape of AGE-RAGE-oxidative stress axis and its modulation by PPARγ activation in high fructose diet-induced metabolic syndrome

Regulatory landscape of AGE-RAGE-oxidative stress axis and its modulation by PPARγ activation in high fructose diet-induced metabolic syndrome

Acute Toxic Effects of Telmisartan in Spontaneously Hypertensive Rats Fed a High Fructose Diet

Dietary Fructose Increases the Sensitivity of Proximal Tubules to Angiotensin II in Rats Fed High-Salt Diets

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