scholarly journals Refining the Mouse Subtotal Nephrectomy in Male 129S2/SV Mice for Consistent Modeling of Progressive Kidney Disease With Renal Inflammation and Cardiac Dysfunction

2019 ◽  
Vol 10 ◽  
Author(s):  
James O’Sullivan ◽  
Sarah Louise Finnie ◽  
Oliver Teenan ◽  
Carolynn Cairns ◽  
Andrew Boyd ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Cardiac Dysfunction ◽  
Renal Inflammation ◽  
Subtotal Nephrectomy

scholarly journals Cardiac Dysfunction in the 5/6 Ablation‐Infarction Model of Chronic Kidney Disease

2013 ◽  
Vol 27 (S1) ◽  
Author(s):  
James M Kuczmarski ◽  
Christopher R Martens ◽  
Shannon L Lennon‐Edwards ◽  
David G Edwards
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Cardiac Dysfunction

scholarly journals Association between Protein-Bound Uremic Toxins and Asymptomatic Cardiac Dysfunction in Patients with Chronic Kidney Disease

Toxins ◽  
2018 ◽  
Vol 10 (12) ◽  
pp. 520 ◽  
Author(s):  
Shanmugakumar Chinnappa ◽  
Yu-Kang Tu ◽  
Yi Chun Yeh ◽  
Griet Glorieux ◽  
Raymond Vanholder ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Cardiac Dysfunction ◽  
Serum Levels ◽  
Significant Negative Correlation ◽  
Cross Sectional Study ◽  
Left Ventricular ◽  
Uremic Toxins ◽  
Cross Sectional ◽  
The Individual

Although the relationship between protein-bound uremic toxins (PBUTs) and cardiac structure and cardiac mortality in chronic kidney disease (CKD) has been studied in the past, the association between cardiac dysfunction and PBUTs has not yet been studied. We therefore evaluated the association between impaired peak cardiac performance and the serum free and total concentrations of potentially cardiotoxic PBUTs. In a cross-sectional study of 56 male CKD patients (stages 2–5 (pre-dialysis)) who were asymptomatic with no known cardiac diseases or diabetes we measured peak cardiac power (CPOmax), aerobic exercise capacity (VO2max), and echocardiographic parameters of cardiac morphology and evaluated their association with PBUTs. The serum total and free concentrations of indoxyl sulfate (IXS), p-cresyl sulfate (PCS), p-cresyl glucuronide, indole acetic acid, and hippuric acid showed significant negative correlation with CPOmax and VO2max. IXS and PCS were independently associated with CPOmax and VO2max even after controlling for eGFR. No correlation between left ventricular mass index (LVMI) and PBUTs was seen. The present study for the first time has demonstrated the association between subclinical cardiac dysfunction in CKD and serum levels of a panel of PBUTs. Further studies are required to evaluate the mechanism of cardiotoxicity of the individual uremic toxins.

scholarly journals Chronic kidney disease with comorbid cardiac dysfunction exacerbates cardiac and renal damage

2017 ◽  
Vol 22 (1) ◽  
pp. 628-645 ◽  
Author(s):  
Shan Liu ◽  
Bing H. Wang ◽  
Darren J. Kelly ◽  
Henry Krum ◽  
Andrew R. Kompa
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Cardiac Dysfunction ◽  
Renal Damage

scholarly journals MO062CHRONIC KIDNEY DISEASE, INFLAMMATION, AND HEART FAILURE WITH PRESERVED EJECTION FRACTION: A RENAL-CARDIO AXIS?

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Alejandro Chade ◽  
Maxx Williams ◽  
Jason Engel ◽  
Gene Bidwell
Keyword(s):  
Heart Failure ◽  
Cardiovascular Risk ◽  
Kidney Disease ◽  
Ejection Fraction ◽  
Diastolic Dysfunction ◽  
Left Ventricular ◽  
Swine Model ◽  
Preserved Ejection Fraction ◽  
Renal Inflammation ◽  
Tnf Α

Abstract Background and Aims Inflammation contributes to progressive renal dysfunction and increases cardiovascular mortality of patients with chronic kidney disease (CKD). The association of CKD and heart failure with preserved ejection fraction (HFpEF) is observed in up to 50%, suggesting the possibility of a shared pathophysiology. CKD and HFpEF are commonly associated with inflammation. Using a novel swine model of CKD and HFpEF, we propose that a renal-cardio inflammatory axis drives diastolic dysfunction and HFpEF in CKD and that targeting renal inflammation will improve cardiac health and reduce cardiovascular risk. Methods We developed a biopolymer-fused peptide of nuclear-factor kappa (NFk)B (ELP-p50i) that we show it blocks its activity in vitro and in vivo. NFkB is a key pro-inflammatory transcription factor that is upregulated in CKD. To test our hypothesis, we induced CKD in 10 pigs via bilateral renovascular disease and dyslipidemia. Pigs were observed for 6 weeks, renal hemodynamics quantified (multi-detector CT), then randomized to single intra-renal ELP-p50i or placebo (n=5 each), and studies repeated 8 weeks later accompanied by echocardiographic assessment. Blood pressure was continuously measured (telemetry). Blood was collected to measure circulating TNF-α and biomarkers of HF (ANP, BNP). Furthermore, kidneys and hearts were used to quantify expression of factors involved in NFkB signaling. Results CKD led to a significant loss of renal function, accompanied by left ventricular hypertrophy and diastolic dysfunction with pEF, increased renal mRNA expression of TNF-α and canonical and non-canonical mediators of NFkB signaling, and elevated systemic TNF-α, ANP, and BNP, indicating renal and cardiac dysfunction. Most of these changes were improved after intra-renal ELP-p50i, although cardiac inflammatory signaling was unchanged (Figure) suggesting the kidney as a source of inflammation that can target the heart in CKD. Conclusion We show that a renal anti-inflammatory strategy via targeted inhibition of renal NFkB improves renal and cardiac function in CKD, suggesting an inflammatory renal-cardio axis. The translational pathological features of CKD and HFpEF combined with the predictive power of the model may contribute to advance the field towards new treatments targeting renal inflammation to reduce cardiovascular risk in CKD.

scholarly journals Tubular STAT3 Limits Renal Inflammation in Autosomal Dominant Polycystic Kidney Disease

2020 ◽  
Vol 31 (5) ◽  
pp. 1035-1049 ◽  
Author(s):  
Amandine Viau ◽  
Maroua Baaziz ◽  
Amandine Aka ◽  
Manal Mazloum ◽  
Clément Nguyen ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Primary Cilia ◽  
Autosomal Dominant ◽  
Polycystic Kidney ◽  
Polycystic Kidneys ◽  
Renal Inflammation ◽  
Tubular Cells ◽  
Autosomal Dominant Polycystic Kidney ◽  
Cyst Growth

BackgroundThe inactivation of the ciliary proteins polycystin 1 or polycystin 2 leads to autosomal dominant polycystic kidney disease (ADPKD). Although signaling by primary cilia and interstitial inflammation both play a critical role in the disease, the reciprocal interactions between immune and tubular cells are not well characterized. The transcription factor STAT3, a component of the cilia proteome that is involved in crosstalk between immune and nonimmune cells in various tissues, has been suggested as a factor fueling ADPKD progression.MethodTo explore how STAT3 intersects with cilia signaling, renal inflammation, and cyst growth, we used conditional murine models involving postdevelopmental ablation of Pkd1, Stat3, and cilia, as well as cultures of cilia-deficient or STAT3-deficient tubular cell lines.ResultsOur findings indicate that, although primary cilia directly modulate STAT3 activation in vitro, the bulk of STAT3 activation in polycystic kidneys occurs through an indirect mechanism in which primary cilia trigger macrophage recruitment to the kidney, which in turn promotes Stat3 activation. Surprisingly, although inactivating Stat3 in Pkd1-deficient tubules slightly reduced cyst burden, it resulted in a massive infiltration of the cystic kidneys by macrophages and T cells, precluding any improvement of kidney function. We also found that Stat3 inactivation led to increased expression of the inflammatory chemokines CCL5 and CXCL10 in polycystic kidneys and cultured tubular cells.ConclusionsSTAT3 appears to repress the expression of proinflammatory cytokines and restrict immune cell infiltration in ADPKD. Our findings suggest that STAT3 is not a critical driver of cyst growth in ADPKD but rather plays a major role in the crosstalk between immune and tubular cells that shapes disease expression.

Delayed spironolactone administration prevents the transition from acute kidney injury to chronic kidney disease through improving renal inflammation

2018 ◽  
Vol 34 (5) ◽  
pp. 794-801 ◽  
Author(s):  
Jonatan Barrera-Chimal ◽  
Leslie Rocha ◽  
Isabel Amador-Martínez ◽  
Rosalba Pérez-Villalva ◽  
Rafael González ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Acute Kidney Injury ◽  
Kidney Disease ◽  
Kidney Injury ◽  
Renal Inflammation

SUPPRESSION OF SIRPα SIGNALING REPLICATES EXERCISE INDUCED REMODELING AND PREVENTS CARDIAC DYSFUNCTION IN CHRONIC KIDNEY DISEASE

2018 ◽  
Vol 71 (11) ◽  
pp. A932
Author(s):  
Giovanni Davogustto ◽  
Jiao Wu ◽  
William Mitch ◽  
Heinrich Taegtmeyer ◽  
Sandhya Thomas
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Cardiac Dysfunction ◽  
Exercise Induced

scholarly journals RIP2 plays a role in cardiac Ca2+ mishandling prompted by chronic kidney disease

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
M Gil-Fernandez ◽  
J.A Navarro-Garcia ◽  
A Val-Blasco ◽  
L Gonzalez-Lafuente ◽  
J.C Martinez ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Cardiac Dysfunction ◽  
Fibroblast Growth Factor 23 ◽  
Funding Source ◽  
Mice Model ◽  
Health Institute ◽  
Major Player ◽  
Genetic Deletion ◽  
Carlos Iii

Abstract Background Chronic kidney disease (CKD) is a multifaceted disease that contributes to cardiac dysfunction. However, the mechanisms underlying the complex relationship between CKD and cardiac impairment remains almost completely unknown. Inflammation is a major player in both CKD and cardiovascular disease (CVD) and, in this context, nucleotide-binding oligomerization domain-containing protein 1 (NOD1) is a newly recognized innate immune receptor involved in both CKD and CVD independently. NOD1 activation is due to the recruitment of the receptor-interacting-serine/threonine-protein kinase 2 (RIP2), which induce NOD1 oligomerization and promotes the inflammatory response, being RIP2 a key partner in the NOD1 activation. Unpublished data from our group has demonstrated that genetic deletion of NOD1 prevents Ca2+ mishandling associated to CKD, next step will be to determine whether the absence of its specific adaptor; RIP2 can also mediate these effects. Purpose The main aim of this study was to determine whether NOD1-RIP2 axis impairs cardiac dysfunction and Ca2+ mishandling prompted by CKD induced by 5/6 nephrectomy (5/6Nx) in a mice model. Methods and results We have analysed intracellular Ca2+ handling in cardiomyocytes obtained from Wild type (Wt), Nod1−/− and Rip2−/− sham operated or nephrectomised mice. Compared with Wt-5/6Nx, cardiomyocytes obtained from Nod1−/−5/6Nx and Rip2−/−5/6Nx mice showed a significant improvement of Ca2+ mishandling, mainly by preventing: i) the reduction in [Ca2+]i transients amplitude; ii) the rise in their decay time; and iii) the lower cell contraction. The lack of NOD1 and RIP2 also prevents the reduced sarcoplasmic reticulum (SR) Ca2+ load and the augmented diastolic Ca2+ leak induced by 5/6Nx. Furthermore, the increased diastolic Ca2+ leak (Ca2+ sparks, spontaneous [Ca2+]i transients and waves) induced by 5/6Nx were also significantly prevented in absence of NOD1 and RIP2. Genetic deletion of NOD1 or RIP2 did not induces any improvement of several markers associated with renal dysfunction (urea, phosphate or fibroblast growth factor-23). Conclusions Our results confirmed that the absence of both NOD1 and RIP2 prevents the intracellular cardiac Ca2+ mishandling in experimental CKD. NOD1 and RIP2 emerge as novel targets for the development of innovative therapeutic strategies for the cardiac remodelling in CKD subjects. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): This work was supported by Spanish ISCIII (PI17/01093 and PI17/01344), Fondo Europeo de Desarrollo Regional (FEDER), FSE, and CIBER-CV, a network funded by ISCIII. MF-V is Miguel Servet II researcher of ISCIII (MSII16/00047 Carlos III Health Institute). GR-H is Miguel Servet I researcher of ISCIII (CP15/00129 Carlos III Health Institute). MT is a PhD student funded by the FPU program of the Spanish Ministry of Science, Innovation and Universities (FPU17/06135).

scholarly journals Cardioprotection Conferred by Sitagliptin Is Associated with Reduced Cardiac Angiotensin II/Angiotensin-(1-7) Balance in Experimental Chronic Kidney Disease

2019 ◽  
Vol 20 (8) ◽  
pp. 1940 ◽  
Author(s):  
Juliana Isa Beraldo ◽  
Acaris Benetti ◽  
Flávio Araújo Borges-Júnior ◽  
Daniel F. Arruda-Junior ◽  
Flavia Letícia Martins ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Angiotensin Ii ◽  
Kidney Disease ◽  
Cardiac Hypertrophy ◽  
Cardiac Dysfunction ◽  
Renin Angiotensin System ◽  
Ckd Progression ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Renal Ablation

Dipeptidyl peptidase IV (DPPIV) inhibitors are antidiabetic agents that exert renoprotective actions independently of glucose lowering. Cardiac dysfunction is one of the main outcomes of chronic kidney disease (CKD); however, the effects of DPPIV inhibition on cardiac impairment during CKD progression remain elusive. This study investigated whether DPPIV inhibition mitigates cardiac dysfunction and remodeling in rats with a 5/6 renal ablation and evaluated if these effects are associated with changes in the cardiac renin-angiotensin system (RAS). To this end, male Wistar rats underwent a 5/6 nephrectomy (Nx) or sham operation, followed by an 8-week treatment period with the DPPIV inhibitor sitagliptin (IDPPIV) or vehicle. Nx rats had lower glomerular filtration rate, overt albuminuria and higher blood pressure compared to sham rats, whereas CKD progression was attenuated in Nx + IDPPIV rats. Additionally, Nx rats exhibited cardiac hypertrophy and fibrosis, which were associated with higher cardiac DPPIV activity and expression. The sitagliptin treatment prevented cardiac fibrosis and mitigated cardiac hypertrophy. The isovolumic relaxation time (IRVT) was higher in Nx than in sham rats, which was suggestive of CKD-associated-diastolic dysfunction. Sitagliptin significantly attenuated the increase in IRVT. Levels of angiotensin II (Ang II) in the heart tissue from Nx rats were higher while those of angiotensin-(1-7) Ang-(1-7) were lower than that in sham rats. This cardiac hormonal imbalance was completely prevented by sitagliptin. Collectively, these results suggest that DPPIV inhibition may delay the onset of cardiovascular impairment in CKD. Furthermore, these findings strengthen the hypothesis that a crosstalk between DPPIV and the renin-angiotensin system plays a role in the pathophysiology of cardiorenal syndromes.

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