Adenine-Induced Chronic Renal Failure in Rats: A Model of Chronic Renocardiac Syndrome with Left Ventricular Diastolic Dysfunction but Preserved Ejection Fraction

Kashioulis, Pavlos; Lundgren, Jaana; Shubbar, Emman; Nguy, Lisa; Saeed, Aso; Guron, Cecilia Wallentin; Guron, Gregor

doi:10.1159/000491056

Cited by 18 publications

(12 citation statements)

References 41 publications

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“…29 To elucidate the effect of the sympathetic nervous system in CKD on atrial remodeling and arrhythmogenesis, we used a rat model of ADinduced kidney damage mimicking CKD in humans. [25][26][27][28] This model exhibited established kidney disease but not end-stage CKD potentially relating to an important group of patients presenting with renal and cardiac comorbidities. 2,6 In our AD-fed rats, the progressive decline of kidney function was accompanied by LA enlargement and interstitial atrial remodeling with increased LA fibrosis formation.…”

Section: Discussionmentioning

confidence: 99%

“…effect of CKD on the development of atrial fibrotic substrates in AF, we compared human LA myocardium from AF patients with and without CKD and respective controls in sinus rhythm (SR). In a translational experimental approach, we used a well-characterized rat model of adenine (AD)-induced kidney damage and CKD [25][26][27][28] to study the impact of renal sympathetic nerve activity on atrial proarrhythmic remodeling. As a therapeutic intervention, we investigated the effect of bilateral RDN on atrial structural remodeling, AF inducibility, and electrical properties.…”

Section: Novelty and Significancementioning

confidence: 99%

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Renal Denervation Prevents Atrial Arrhythmogenic Substrate Development in CKD

Hohl

Selejan

Wintrich

et al. 2022

Circulation Research

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Background: In patients with chronic kidney disease (CKD), atrial fibrillation (AF) is highly prevalent and represents a major risk factor for stroke and death. CKD is associated with atrial proarrhythmic remodeling and activation of the sympathetic nervous system. Whether reduction of the sympathetic nerve activity by renal denervation (RDN) inhibits AF vulnerability in CKD is unknown. Methods: Left atrial (LA) fibrosis was analyzed in samples from patients with AF and concomitant CKD (estimated GFR, <60 mL/min per 1.73 m 2 ) using picrosirius red and compared with AF patients without CKD and patients with sinus rhythm with and without CKD. In a translational approach, male Sprague Dawley rats were fed with 0.25% adenine (AD)-containing chow for 16 weeks to induce CKD. At week 5, AD-fed rats underwent RDN or sham operation (AD). Rats on normal chow served as control. After 16 weeks, cardiac function and AF susceptibility were assessed by echocardiography, radiotelemetry, electrophysiological mapping, and burst stimulation, respectively. LA tissue was histologically analyzed for sympathetic innervation using tyrosine hydroxylase staining, and LA fibrosis was determined using picrosirius red. Results: Sirius red staining demonstrated significantly increased LA fibrosis in patients with AF+CKD compared with AF without CKD or sinus rhythm. In rats, AD demonstrated LA structural changes with enhanced sympathetic innervation compared with control. In AD, LA enlargement was associated with prolonged duration of induced AF episodes, impaired LA conduction latency, and increased absolute conduction inhomogeneity. RDN treatment improved LA remodeling and reduced LA diameter compared with sham-operated AD. Furthermore, RDN decreased AF susceptibility and ameliorated LA conduction latency and absolute conduction inhomogeneity, independent of blood pressure reduction and renal function. Conclusions: In an experimental rat model of CKD, RDN inhibited progression of atrial structural and electrophysiological remodeling. Therefore, RDN represents a potential therapeutic tool to reduce the risk of AF in CKD, independent of changes in renal function and blood pressure.

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Section: Discussionmentioning

confidence: 99%

Section: Novelty and Significancementioning

confidence: 99%

Renal Denervation Prevents Atrial Arrhythmogenic Substrate Development in CKD

Hohl

Selejan

Wintrich

et al. 2022

Circulation Research

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“…With semi-auto contouring, the left and RV endocardium and epicardium at the end of diastole from conventional CMR cine image, myocardial tissue tracking strain, and strain rate were determined automatically (21). Compared with ultrasound speckle tracking imaging technology, CMR-TT is not affected by imaging angle, can directly observe morphological changes of the ventricle, and obtain two-ventricular free wall myocardial strain (22)(23)(24)(25)(26). In conditions leading to RV pressure or volume overloads such as pulmonary hypertension, tetralogy of Fallot, or Systemic RV, the contractile pattern changes from longitudinal to circumferential shortening (27,28).…”

Section: Discussionmentioning

confidence: 99%

Age- and gender-related normal references of right ventricular strain values by tissue tracking cardiac magnetic resonance: results from a Chinese population

Liu¹,

Wang²,

Li³

et al. 2019

Quant. Imaging Med. Surg.

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Background: Myocardial deformation is a sensitive marker for sub-clinical myocardial dysfunction and carries independent prognostic significance across a broad range of cardiovascular diseases. Reproducible and repeatable assessment of right ventricular (RV) function is vital for monitoring congenital and acquired heart diseases. The purpose of this study was to determine the normal references of RV strain and strain rate values using tissue tracking cardiac magnetic resonance imaging (MRI). Methods: A cohort of 120 normal human subjects from each decade of life between 20 and 70 without cardiac diseases were enrolled in this study. Retrospectively, electrocardiogram (ECG) gating cardiac MRI imaging was performed at 3.0T with balanced steady-state free precession (bSSFP) imaging. RV global and segmental myocardial strains were analyzed by tissue tracking by two experienced observers. Results: The global peak longitudinal strain (GLS) and global peak radial strain (GRS) was −24.3±4.7 and 23.0±8.5 respectively. For the peak circumferential strains (GCS), the values for global, basal, mid-cavity, and apical segments were −13.3±4.1, −13.1±4.0, −12.5±4.7, and −15.9±5.8, respectively. There were significant gender differences in peak GRS (P=0.009) and at the base (P=0.017) and the mid-cavity (P=0.011) with greater deformation in females than in males. There were also significant age differences in GRS (P<0.001), GCS for basal (P<0.001), and mid-cavity segments (P=0.037). On Bland-Altman analysis, peak GLS and GRS had the best intra-observer agreement (mean bias, −0.13±0.51; 95% CI, −1.13-0.87) and inter-observer (mean bias, 0.054±0.31; 95% CI, −0.55-0.66) agreement, respectively. Conclusions: Normal values of RV deformation for healthy individuals using tissue tracking cardiac magnetic resonance (CMR-TT) provided good RV peak strain reproducibility. There was a significant correlation between RV strain or strain rate parameters with either age or sex.

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“…Adenine causes chronic renal failure in rats, which manifests as severe renal insu ciency and metabolic abnormalities that are very similar to those seen in uremic people (Kashioulis et al, 2018). Additionally, mesangial enlargement, endothelial dysfunction, and glomerular brosis are caused by cellular oxidative stress associated with CRF (Daenen et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Is MCC950, an NLRP3 inflammasome inhibitor, a renopreventive: A chronic renal failure adenine model in rats

Sabra

Hemida

Allam

2023

Preprint

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Background: Chronic renal failure (CRF) is characterized by a great loss in renal function ending with reduced sodium filtration and suppression of tubular reabsorption that eventually leads to volume expansion. The contradictory information on the MCC950 renal effects brought this study to evaluate the possible renopreventive effects of NLRP3 inflammasome inhibitor MCC950 in adenine-induced CRF in rats. Methods: Adding 0.75% of adenine powder to a rat’s ration daily for 4 weeks is measured as a broad approval to be a model of evaluation of kidney damage as it is similar to most of the kidney tubular alterations seen in chronic kidney-diseased patients. Blood pressure was monitored at baseline and weekly during the test. Also, oxidative stress factors, urine sample analysis, histopathological changes, and immunohistochemical alterations of caspase-3 and interleukin-1 beta (IL-1β) levels in renal tissues were done. Results: Results showed that the NLRP3 inflammasome inhibitor MCC950 had a renopreventive effect that was established by a decrease in blood pressure measurements, and improvement of urinary, serum, and renal tissue markers as revealing organ damage. This was also revealed by the reduction of tubular expression of neutrophil gelatinase-associated lipocalin (NGAL). Immunohistochemical studies revealed that the worsened renal cellular changes indicated by raised expression of caspase-3 and IL-1β were prominently improved by NLRP3 inflammasome inhibitor MCC950 administration. Conclusion: The NLRP3 inflammasome inhibitor MCC950 administration in the CRF rat model had renopreventive effects which may be a potential therapeutic approach to prevent the progression of CRF.

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Adenine-Induced Chronic Renal Failure in Rats: A Model of Chronic Renocardiac Syndrome with Left Ventricular Diastolic Dysfunction but Preserved Ejection Fraction

Cited by 18 publications

References 41 publications

Renal Denervation Prevents Atrial Arrhythmogenic Substrate Development in CKD

Renal Denervation Prevents Atrial Arrhythmogenic Substrate Development in CKD

Age- and gender-related normal references of right ventricular strain values by tissue tracking cardiac magnetic resonance: results from a Chinese population

Is MCC950, an NLRP3 inflammasome inhibitor, a renopreventive: A chronic renal failure adenine model in rats

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