Coexistence of chronic kidney disease (CKD) and heart failure (HF) in humans is associated with poor outcome. We hypothesized that preexistent CKD worsens cardiac outcome after myocardial infarction, ...and conversely that ensuing HF worsens progression of CKD. Subtotally nephrectomized (SNX) or sham-operated (CON) rats were subjected to coronary ligation (CL) or sham surgery in week 9 to realize four groups: CON, SNX, CON + CL, and SNX + CL. Blood pressure and renal function were measured in weeks 8, 11, 13, and 15. In week 16, cardiac hemodynamics and end-organ damage were assessed. Blood pressure was significantly lower in SNX + CL vs. SNX. Despite this, glomerulosclerosis was more severe in SNX + CL vs. SNX. Two weeks after CL, SNX + CL had more cardiac dilatation compared with CON + CL (end-diastolic volume index: 0.28 ± 0.04 vs. 0.19 ± 0.03 ml/100 g body wt; mean ± SD, P < 0.001), although infarct size was similar. During follow-up in SNX + CL, ejection fraction declined. Mortality was only observed in SNX + CL (2 out of 9). In SNX + CL, end-diastolic pressure (18 ± 4 mmHg) and tau (29 ± 9 ms), the time constant of active relaxation, were significantly higher compared with SNX (13 ± 3 mmHg, 20 ± 4 ms; P < 0.01) and CON + CL (11 ± 5 mmHg, 17 ± 2 ms; P < 0.01). The diameter of small arterioles in the myocardium was significantly decreased in SNX + CL vs. CON + CL (P < 0.01). Urinary excretion of NO metabolites was significantly lower in SNX + CL compared with both CL and SNX. This study demonstrates the existence of more heart and more kidney damage in a new model of combined CKD and HF than in the individual models. Such enhanced damage appears to be separate from systemic hemodynamic changes. Reduced nitric oxide availability may have played a role in both worsened glomerulosclerosis and cardiac diastolic function and appears to be a connector in the cardiorenal syndrome.
OBJECTIVE:It is well established that autonomic nervous system and sympatho-vagal balance plays an important role in maintaining arterial blood pressure (ABP) (Salman IM., 2016) and that autonomic ...regulation of ABP differs between males and females (Hart EC et al., 2014). We hypothesised that sex hormones affect blood pressure via the autonomic nervous system and that the late development of hypertension in females is due to protective effects of ovarian steroids in females rather than due to detrimental effects of testosterone in males.
DESIGN AND METHOD:We used adult, 12 months old, Wistar female and male, intact and gonadectomised rats (n = 8, per each group). Resting ABP was recorded by radio-telemetry. Heart rate (HR) and ABP variability were calculated using Spike2 software. Effect of gender and gonadectomy were assessed by two-way Anova.
RESULTS:Females had lower systolic (S)BP compared to males (121 ± 1 vs 128 ± 2 mmHg; P < 0.05). Intact (81 ± 2 mmHg) but not ovariectomised (89 ± 2 mmHg) females had lower diastolic (D)BP compared to males (91 ± 1 mmHg; P < 0.01). Moreover, intact (353 ± 6bpm) but not ovariectomised (307 ± 5 bpm) females had higher HR compared to males (353 ± 6bpm; P < 0.001). However, ovariectomy did not influence the higher respiratory rate in females vs males (91 ± 3 vs 78 ± 3 bpm; P < 0.001).Power spectra analysis of SBP shows that males (22.4 ± 3) and ovariectomised females (26.9 ± 3) had lower High Frequency percentage vs females (38 ± 3; P < 0.05) suggesting that female hormones affect ABP by modulating the parasympathetic activity. The Very Low Frequency percentage was higher in males vs females (40 ± 4 vs 28 ± 4; P < 0.05) suggesting that sympathetic vasomotor tone might play an important role in the differential regulation of SBP between males and females.
CONCLUSIONS:Altogether, this results show that female hormones have a positive effect on ABP and that they affect ABP via modulating parasympathetic activity. Further analyses of BP and HR variability at different ages are needed to determine the interaction between age, BP and gender.
IL-6 has pro- and anti-inflammatory effects and is involved in endothelial cell (EC) dysfunction. The anti-inflammatory effects of IL-6 are mediated by signal transducer and activator of ...transcription-3 (STAT3), which is importantly controlled by suppressor of cytokine signaling 3 (SOCS3). Therefore, cytokines that modulate SOCS3 expression might inhibit the anti-inflammatory effects of IL-6. We hypothesized that in EC, interferon-gamma (IFNgamma)-induced SOCS3 expression leads to inhibition of IL-6-induced STAT3 activation and IL-6-dependent expression of anti-, but not pro-inflammatory, target genes. IFNgamma activated STAT1 and STAT3 and increased SOCS3 expression in EC. IL-6 only activated STAT3 and induced SOCS3 expression. IFNgamma pretreatment of EC inhibited IL-6-induced STAT3 activation accompanied by increased SOCS3 protein. Inhibition of SOCS3 expression, using costimulation, Act-D, and small interfering RNA (siRNA), subsequently implicated the importance of IFNgamma-induced SOCS3 in this phenomenon. Pretreatment of EC with IFNgamma also affected the transcriptional program induced by IL-6. We identified 1) IL-6 anti-inflammatory target genes that were inhibited by IFNgamma, 2) IFNgamma-target genes of pro-inflammatory nature that were increased in response to IL-6 in the presence of IFNgamma, and 3) a set of target genes that were increased upon IL-6 or IFNgamma alone, or combined IFNgamma and IL-6. In summary, by increasing SOCS3 expression in EC, IFNgamma can selectively inhibit STAT3-dependent IL-6 signaling. This in turn leads to decreased expression of some EC protective genes. In contrast, other genes of pro-inflammatory nature are not inhibited or even increased. This IFNgamma-induced shift in IL-6 signaling to a pro-inflammatory phenotype could represent a novel mechanism involved in EC dysfunction.
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Chronic nitric oxide (NO) depletion induces hypertension and renal damage. Chronic kidney disease is associated with decreased NO availability and less renal H
2
S production. We ...hypothesized that combined depletion of NO and H
2
S aggravates hypertension and renal injury. Male 8-wk old Sprague Dawley rats were treated with vehicle, NO synthase inhibitor L-NG-nitroarginine (LNNA; 125 mg/L in drinking water), cystathionine-γ-lyase (CSE) inhibitor propargylglycine (PAG; 37.5 mg/kg BW ip daily) or LNNA
+
PAG for 1 and 4 weeks (6 rats/group). LNNA after 4w increased systolic blood pressure (SBP; 223±10
vs
. 137±3 mmHg in controls; P<0.01), proteinuria (144±35
vs.
17±2 mg/d; P<0.01), uremia (16.6±4.2
vs
. 7.0±0.4 mmol/L; P<0.05) and tubulo-interstitial injury (P<0.01). LNNA reduced urinary NO metabolite (NOx) excretion by ∼85% after 1w and 4w. PAG alone had no effect on SBP, renal function or injury, but did reduce urinary NOx excretion. Co-treatment with PAG ameliorated LNNA-induced hypertension (182±10 mmHg; P<0.01) and prevented proteinuria (27±3 mg/d), uremia (8.3±0.4 mmol/L) and tubulo-interstitial injury, but did not further reduce urinary NOx excretion. Renal H
2
S production was almost absent in all PAG groups after 1w and 4w (P<0.01) and was reduced in LNNA-treated rats after 4w (4.6±1.4
vs
. 9.2±0.5 μmol/hr/mg; P<0.01). Renal HO-1 gene expression was strongly induced in all PAG-treated groups after 1w and 4w (4 to 19-fold; P<0.01) whereas LNNA only increased HO-1 gene expression at 4w (P<0.01). Immunohistochemistry showed that renal HO-1 protein was primarily interstitial in all PAG-treated groups at 1w and 4w. In contrast, LNNA only showed HO-1 in tubular epithelium in conjunction with protein casts. Depleting NO caused hypertension and renal damage followed by reduced renal H
2
S production and increased renal HO-1 expression. Surprisingly, concomitant inhibition of CSE ameliorated hypertension and prevented renal injury. PAG almost completely blocked renal H
2
S production and caused strong induction of renal HO-1, independently of injury, suggesting that H
2
S suppresses renal HO-1 expression. In conclusion, concomitant upregulation of HO-1 expression by inhibition of H
2
S production, prevents LNNA-induced hypertension and renal injury.
Sexual dimorphism in blood pressure has been associated with differential expression of the angiotensin II (AII) receptors and with activity of the nervous system. It is generally accepted that ...ageing affects kidney function as well as autonomic nervous system and hormonal balance. Given that hypertension is more prevalent in men than women until women reach their seventh decade, we hypothesised that females would be relatively protected from adverse effects of ageing compared to males and that this would be mediated by the protective effect of ovarian steroids.
Intact and gonadectomised male and female normotensive Wistar rats aged 6, 12 and 18 months were used to study renal function, blood pressure, heart rate, and blood pressure variability.
We observed that intact females had lower levels of proteinuria and higher (12.5%) creatinine clearance compared to intact males and that this difference was abolished by castration but not by ovariectomy. Ovariectomy resulted in a change by 9% in heart rate, resulting in similar cardiovascular parameters to those observed in males or gonadectomised males. Spectral analysis of systolic blood pressure revealed that high-frequency power spectra were significantly elevated in the females vs. males and were reduced by ovariectomy.
Taken altogether, the results show that females are protected from age-related declining renal function and to a lesser extent from rising blood pressure in comparison to males. Whilst ovariectomy had some deleterious effects in females, the strongest effects were associated with gonadectomy in males, suggesting a damaging effect of male hormones.
The effect of the flavonoid quercetin and its conjugate rutin was investigated on (biomarkers of) colorectal cancer (CRC). Male F344 rats (n = 42/group) were fed 0, 0.1, 1, or 10 g quercetin/kg diet ...or 40 g rutin/kg diet. Two wk after initial administration of experimental diets, rats were given 2 weekly subcutaneous injections with 15 mg/kg body wt azoxymethane (AOM). At wk 38 post-AOM, quercetin dose dependently (P < 0.05) decreased the tumor incidence, multiplicity, and size, whereas tumor incidences were comparable in control (50%) and rutin (45%) groups. The number of aberrant crypt foci (ACF) in unsectioned colons at wk 8 did not correlate with the tumor incidence at wk 38. Moreover, at wk 8 post-AOM, the number and multiplicity of ACF with or without accumulation of β-catenin were not affected by the 10 g quercetin/kg diet. In contrast, another class of CRC-biomarkers, β-catenin accumulated crypts, contained less β-catenin than in controls (P < 0.05). After enzymatic deconjugation, the plasma concentration of 3'-O-methyl-quercetin and quercetin at wk 8 was inversely correlated with the tumor incidence at wk 38 (r = -0.95, P <= 0.05). Rats supplemented with 40 g rutin/kg diet had only 30% of the (3'-O-methyl-) quercetin concentration of 10 g quercetin/kg diet-fed rats (P < 0.001). In conclusion, quercetin, but not rutin, at a high dose reduced colorectal carcinogenesis in AOM-treated rats, which was not reflected by changes in ACF-parameters. The lack of protection by rutin is probably due to its low bioavailability.
The aging kidney exhibits a progressive decline in glomerular filtration rate, accompanied by inflammatory and oxidative damage. We hypothesized that accelerated, age‐related progression of renal ...injury is ovarian hormones‐dependant. To address this we used an established model of developmentally programmed accelerated renal aging in the rat, superimposed by ovariectomy to assess interactions between ovarian hormones and the aging process. Under our experimental conditions, we found that kidney function worsens with age, that is GFR reduces over 18 month analyzed time‐course and this was worsened by fetal exposure to maternal low‐protein diet and absence of estrogen. Reduction in GFR was followed by increases in albuminuria, proteinuria, inflammatory markers, and tissue carbonyls, all suggesting inflammatory response and oxidative stress. This was associated with changes in AGTR2 expression which was greater at 18 months of age compared to earlier time points, but in MLP offspring only. Our studies show an influence of ovarian hormones on programmed accelerated renal aging and the AGTR2 across the lifespan. The main findings are that ovariectomy is a risk factor for increased aging‐related renal injury and that this and oxidative damage might be related to changes in AGTR2 expression.
Compared to males, females are relatively protected against renal aging. We hypothesized that up‐regulation of the angiotensin II (AGTR2) receptor in the kidney ameliorates progression of renal injury and hypertension, and that this is estrogen‐dependent. The main finding was that renal injury was related to AGTR2 expression and that ovariectomy increased age‐related deterioration of renal function.
IL-6 has pro- and anti-inflammatory effects and is involved in endothelial cell (EC) dysfunction. The anti-inflammatory effects of IL-6 are mediated by signal transducer and activator of ...transcription-3 (STAT3), which is importantly controlled by suppressor of cytokine signaling 3 (SOCS3). Therefore, cytokines that modulate SOCS3 expression might inhibit the anti-inflammatory effects of IL-6. We hypothesized that in EC, interferon-γ (IFNγ)-induced SOCS3 expression leads to inhibition of IL-6-induced STAT3 activation and IL-6-dependent expression of anti-, but not pro-inflammatory, target genes. IFNγ activated STAT1 and STAT3 and increased SOCS3 expression in EC. IL-6 only activated STAT3 and induced SOCS3 expression. IFNγ pretreatment of EC inhibited IL-6-induced STAT3 activation accompanied by increased SOCS3 protein. Inhibition of SOCS3 expression, using costimulation, Act-D, and small interfering RNA (siRNA), subsequently implicated the importance of IFNγ-induced SOCS3 in this phenomenon. Pretreatment of EC with IFNγ also affected the transcriptional program induced by IL-6. We identified 1) IL-6 anti-inflammatory target genes that were inhibited by IFNγ, 2) IFNγ-target genes of pro-inflammatory nature that were increased in response to IL-6 in the presence of IFNγ, and 3) a set of target genes that were increased upon IL-6 or IFNγ alone, or combined IFNγ and IL-6. In summary, by increasing SOCS3 expression in EC, IFNγ can selectively inhibit STAT3-dependent IL-6 signaling. This in turn leads to decreased expression of some EC protective genes. In contrast, other genes of pro-inflammatory nature are not inhibited or even increased. This IFNγ-induced shift in IL-6 signaling to a pro-inflammatory phenotype could represent a novel mechanism involved in EC dysfunction. PUBLICATION ABSTRACT
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