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Chronic kidney disease with comorbid cardiac dysfunction exacerbates cardiac and renal damage.

ABSTRACT: To address the pathophysiological mechanisms underlying chronic kidney disease with comorbid cardiac dysfunction, we investigated renal and cardiac, functional and structural damage when myocardial infarction (MI) was applied in the setting of kidney injury (induced by 5/6 nephrectomy-STNx). STNx or Sham surgery was induced in male Sprague-Dawley rats with MI or Sham surgery performed 4 weeks later. Rats were maintained for a further 8 weeks. Rats (n = 36) were randomized into four groups: Sham+Sham, Sham+MI, STNx+Sham and STNx+MI. Increased renal tubulointerstitial fibrosis (P < 0.01) and kidney injury molecule-1 expression (P < 0.01) was observed in STNx+MI compared to STNx+Sham animals, while there were no further reductions in renal function. Heart weight was increased in STNx+MI compared to STNx+Sham or Sham+MI animals (P < 0.05), despite no difference in blood pressure. STNx+MI rats demonstrated greater cardiomyocyte cross-sectional area and increased cardiac interstitial fibrosis compared to either STNx+Sham (P < 0.01) or Sham+MI (P < 0.01) animals which was accompanied by an increase in diastolic dysfunction. These changes were associated with increases in ANP, cTGF and collagen I gene expression and phospho-p38 MAPK and phospho-p44/42 MAPK protein expression in the left ventricle. Addition of MI accelerated STNx-induced structural damage but failed to significantly exacerbate renal dysfunction. These findings highlight the bidirectional response in this model known to occur in cardiorenal syndrome (CRS) and provide a useful model for examining potential therapies for CRS.

SUBMITTER: Liu S

PROVIDER: S-EPMC5742721 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Chronic kidney disease with comorbid cardiac dysfunction exacerbates cardiac and renal damage.

Liu Shan S Wang Bing H BH Kelly Darren J DJ Krum Henry H Kompa Andrew R AR

Journal of cellular and molecular medicine 20171010 1

To address the pathophysiological mechanisms underlying chronic kidney disease with comorbid cardiac dysfunction, we investigated renal and cardiac, functional and structural damage when myocardial infarction (MI) was applied in the setting of kidney injury (induced by 5/6 nephrectomy-STNx). STNx or Sham surgery was induced in male Sprague-Dawley rats with MI or Sham surgery performed 4 weeks later. Rats were maintained for a further 8 weeks. Rats (n = 36) were randomized into four groups: Sham+ ...[more]

PMID: 28994186

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Project description:Background and objectiveIncreased renal venous pressure (RVP) is common in combined heart and kidney failure. We previously showed that acute RVP elevation depresses renal blood flow (RBF), glomerular filtration rate (GFR), and induces renal vasoconstriction in the absence of changes in blood pressure in healthy rats. We used our established rodent model of chronic combined heart and kidney failure (H/KF) to test whether RVP elevation would impair cardiovascular stability, renal perfusion and exacerbate renal dysfunction.MethodsMale rats were subjected to 5/6 nephrectomy (SNx or Sham) and 6% high salt diet followed 7 weeks later by ligation of the left anterior descending coronary artery (CL or Sham). Experimental groups: CL + SNx (n = 12), Sham CL + SNx (n = 9), CL+ Sham SNx (n = 6), and Sham Control (n = 6). Six weeks later, anesthetized rats were subjected to an acute experiment whereupon mean arterial pressure (MAP), heart rate (HR), RVP, RBF, and GFR were measured at baseline and during elevation of RVP to 20-25 mmHg for 120 min.ResultsBaseline MAP, HR, RBF, and renal vascular conductance (RVC) were comparable among groups. Baseline GFR was significantly depressed in CL + SNx and Sham CL + SNx groups compared to Sham Control and CL + Sham SNx groups. Upon RVP increase, MAP and HR fell in all groups. Increased RVP exacerbated the reduction in RBF in CL + SNx (-6.4 ± 0.9 ml/min) compared to Sham Control (-3.7 ± 0.9 ml/min, p < 0.05) with intermediate responses in Sham CL + SNx (-6.8 ± 1.3 ml/min) and CL + Sham SNx (-5.1 ± 0.4 ml/min) groups. RVP increase virtually eliminated GFR in CL + SNx (-99 ± 1%), Sham CL + SNx (-95 ± 5%), and CL + Sham SNx (-100%) groups compared to Sham Control (-84 ± 15% from baseline; p < 0.05). Renal vascular conductance dropped significantly upon RVP increase in rats with HF (CL + SNx: -0.035 ± 0.011; CL + Sham SNx: -0.050 ± 0.005 ml/min·mmHg-1, p < 0.05) but not Sham CL + SNx (-0.001 ± 0.019 ml/min·mmHg-1) or Control (-0.033 ± mL/min·mmHg-1).ConclusionChronic combined heart and kidney failure primarily impairs renal hemodynamic stability in response to elevated RVP compared to healthy rats.

Project description:Background: Short-chain fatty acids (SCFAs), mainly acetate, propionate and butyrate, are produced by gut microbiota through fermentation of complex carbohydrates that cannot be digested by the human host. They affect gut health and can contribute at the distal level to the pathophysiology of several diseases, including renal pathologies. Methods: SCFA levels were measured in chronic kidney disease (CKD) patients (n = 54) at different stages of the disease and associations with renal function and inflammation parameters were examined. The impact of propionate and butyrate in pathways triggered in tubular cells under inflammatory conditions was analysed using genome-wide expression assays. Finally, a pre-clinical mouse model of folic acid-induced transition from acute kidney injury to CKD was used to analyse the preventive and therapeutic potential of these microbial metabolites in the development of CKD. Results: Faecal levels of propionate and butyrate in CKD patients gradually reduce as the disease progresses, and do so in close association with established clinical parameters for serum creatinine, blood urea nitrogen and the estimated glomerular filtration rate. Propionate and butyrate jointly downregulated the expression of 103 genes related to inflammatory processes and immune system activation triggered by TNF-α in tubular cells. In vivo, the administration of propionate and butyrate, either before or soon after injury, respectively prevented and slowed the progression of damage. This was indicated by a decrease in renal injury markers, the expression of pro-inflammatory and pro-fibrotic markers, and recovery of renal function over the long term. Conclusions: Propionate and butyrate levels are associated with a progressive loss of renal function in CKD patients. Early administration of these SCFAs prevents disease advancement in a pre-clinical model of acute renal damage, demonstrating their therapeutic potential independently of the gut microbiota.

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Chronic kidney disease with comorbid cardiac dysfunction exacerbates cardiac and renal damage.

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Chronic kidney disease with comorbid cardiac dysfunction exacerbates cardiac and renal damage.

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