Aberrant carotid body chemoreceptor (CBC) function contributes to increased sympathetic nerve activity (SNA) and reduced renal blood flow (RBF) in chronic heart failure (CHF). Intermittent asphyxia (IA) mimicking sleep apnea is associated with additional increases in SNA and may worsen reductions in RBF and renal PO2 (RPO2) in CHF. The combined effects of decreased RBF and RPO2 may contribute to biochemical changes precipitating renal injury. This study sought to determine the role of CBC activity on glomerular filtration rate (GFR), RBF and RPO2 in CHF, and to assess the additive effects of IA. Furthermore, we sought to identify changes in gene expression that might contribute to renal injury. We hypothesized that GFR, RBF, and RPO2 would be reduced in CHF, that decreases in RBF and RPO2 would be worsened by IA, and that these changes would be ameliorated by CBC ablation (CBD). Finally, we hypothesized that CHF would be associated with pro-oxidative pro-fibrotic changes in renal gene expression that would be ameliorated by CBD. CHF was induced in adult male Sprague Dawley rats using coronary artery ligation (CAL). Carotid body denervation was performed by cryogenic ablation. GFR was assessed in conscious animals at the beginning and end of the experimental period. At 8-weeks post-CAL, cardiac function was assessed via echocardiography, and GFR, baseline and IA RBF and RPO2 were measured. Renal gene expression was measured using qRT-PCR. GFR was lower in CHF compared to sham (p < 0.05) but CBD had no salutary effect. RBF and RPO2 were decreased in CHF compared to sham (p < 0.05), and this effect was attenuated by CBD (p < 0.05). RBF and RPO2 were reduced to a greater extent in CHF vs. sham during exposure to IA (p < 0.05), and this effect was attenuated by CBD for RBF (p < 0.05). Downregulation of antioxidant defense and fibrosis-suppressing genes was observed in CHF vs. sham however CBD had no salutary effect. These results suggest that aberrant CBC function in CHF has a clear modulatory effect on RBF during normoxia and during IA simulating central sleep apnea.
Introduction Type II cardiorenal syndrome (CRSII) is characterized by declining renal function in the face of chronic heart failure (CHF). Abnormal renal hemodynamics and neurohormonal activation are thought to play prominent roles in this process and are initiated in part via aberrant carotid body chemoreflex‐mediated (CBC) increases in sympathetic nerve activity. Sleep apnea (SA) is a common comorbidity in CHF patients and is independently associated with renal dysfunction. Chronic intermittent hypoxia (CIH) in SA may play a key role in driving development of CRSII as it adversely affects CBC function, autonomic control, renal hemodynamics, and renal oxygen flux. In this study, we sought to determine if CIH has additive effects in CHF that hasten the decline of renal function, and if this is mediated by the CBC. Hypothesis CIH will exacerbate reductions in renal blood flow (RBF), glomerular filtration rate (GFR), and renal tissue oxygenation (RPO2) in CHF, and carotid body denervation (CBD) will attenuate these changes. Methods Adult male SD rats (n=7‐10/group) were randomly assigned to sham, CHF, CHF‐CIH, and CHF‐CIH‐CBD groups. CHF was induced by ligation of the LAD coronary artery (CAL), and cardiac function was assessed in all groups via M‐mode echocardiography. CBD was performed 4 weeks post‐CAL, while RBF (Transonic), RPO2 (Oxford Optronix Oxylite), and GFR (Medibeacon) were measured at 8‐weeks post‐CAL. Results RBF was significantly decreased (p<0.05) in CHF and CHF CIH groups relative to sham (0.024±0.002 ml/min/gBW sham vs. 0.013±0.001 ml/min/gBW CHF, and 0.012±0.002 ml/min/gBW CHF‐CIH). CBD significantly attenuated the reductions in RBF in the CHF CIH group(0.017±0.002 ml/min/gBW CHF CIH CBD, p<0.05 vs. CHF CIH). Cortical RPO2 decreased in CHF relative to sham (39±3 mmHg sham vs. 28±2 mmHg CHF, p<0.05), but was not significantly lower in CHF‐CIH (23.4±4.3). CBD attenuated decreases in cortical RPO2 in CHF‐CBD‐CIH (39±3 mmHg, p<0.05 vs. CHF CIH). GFR was lower in CHF vs. sham (0.92±0.07 vs. 1.30±0.13, p<0.05) but not significantly lower in CHF CIH vs. CHF (0.89±0.06 vs. 0.92±0.07) . GFR was lowest in CHF CIH CBD (0.76±0.05 ml/min/100g, p<0.05 vs. CHF and CHF CIH). Conclusions CBD improved renal perfusion and PO2 in CHF animals exposed to CIH but failed to improve GFR. Additional hypoxic stress due to a blunted hypoxic ventilatory response during CIH may result in renal damage/nephron loss that counter‐balances any beneficial effect that CBD has on RBF in CHF. These results suggest a complex interplay between chemoreflex activity and renal hemodynamics in CHF and the diffuse effects of concomitant CIH.
Background and RationaleSleep apnea (SA) is associated with hypertension and chronic kidney disease. Dysregulation of blood pressure control and renal damage may occur because of the chronic intermittent hypoxia (CIH) that occurs during SA. Reductions in renal blood flow (RBF) during or after CIH may lead to renal injury by contributing to recurrent tissue hypoxia and alterations in shear‐stress (SS) related signaling. Krüppel‐like factor 2 (KLF2) is a SS‐sensitive transcription factor that controls expression of antioxidant and anti‐inflammatory gene programs.HypothesisWe hypothesized that CIH would result in baseline reductions in RBF and exacerbate subsequent reductions in RBF during hypoxia. Furthermore, renal KLF2 expression will be reduced along with attendant changes in its downstream targets.MethodsAdult male Sprague Dawley rats were exposed to 10 days CIH (60 sec. 10% O2, 120 sec. 21% O2) for 8h/d. Post‐CIH (or sham) RBF was measured using Transonic flow probes before, during, and after exposure to 10% O2. After euthanasia, renal cortical and medullary tissue was probed for expression of KLF2, interleukin 6 (IL‐6), superoxide dismutase (SOD1), neutrophil gelatinase‐associated lipocalin (NGAL) via western blot.ResultsBaseline weight‐corrected RBF was lower in CIH vs. sham (1.89±0.13 mL/min/g vs. 1.42±0.16 mL/min/g, p<0.05), and the RBF response to 10% O2 was accentuated in CIH vs. sham (−45±14% CIH vs. −26±4% sham, p<0.05). During recovery, RBF at 20 min post‐hypoxia remained below baseline values in both groups (93±3% of baseline sham vs. 85±4% of baseline CIH, P>0.05). Ten consecutive episodes of 10% O2 elicited reductions in RBF that persisted after return to 21% oxygen and which were significantly reduced from baseline for the duration of the exposure period (p<0.05). Cortical and medullary KLF2 expression were decreased by 40–50% in CIH relative to sham (1.00±0.21 sham cortex vs. 0.46±0.08 CIH cortex, and 1.00±0.24 sham medulla vs. 0.44±0.10 CIH medulla, p<0.05 for both comparisons). Cortical SOD1 expression was reduced in CIH relative to sham (1.00±0.00 sham vs. 0.72±0.12 CIH, p<0.05), whereas IL‐6 expression was increased (1.00±0.19 sham vs. 1.56±0.21 CIH cortex, p<0.05). Medullary NGAL was increased in CIH vs. sham (p<0.05).ConclusionPersistent reductions in RBF during and after apneic episodes (CIH) may contribute to renal inflammation, oxidative stress, and injury via downregulation of KLF2.Support or Funding InformationSupported by a grant from NHLBI (R15 HL138600‐01 to NJM)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Background and SignificanceRecent evidence suggests aberrant carotid body chemoreceptor (CBC) function contributes to tonic elevation of renal nerve activity and reductions in renal blood flow in chronic heart failure (CHF). These changes combined with anemia and capillary rarefaction likely contribute to tissue hypoxia, and may drive renal fibrosis and attendant dysfunction. Previous work indicates that stable expression of hypoxia‐inducible factor 1‐α (HIF1α) and down regulation of MiR‐155 drive gene programs that mediate epithelial‐mesenchymal transition (EMT) in renal tubular epithelial cells, including increases in Krüppel‐like factor 4 (KLF4) and matrix metalloproteinase 9 (MMP9). To date, no studies have examined this signaling pathway in CHF, thus our objective was to determine the influence of CBC on renal cortical expression of HIF1α, KLF4, MiR‐155, MMP9, and α‐smooth muscle actin (SMA) in CHF.HypothesisWe hypothesize that CBC‐mediated reductions in renal blood flow activate EMT pathways in CHF by exacerbating tissue hypoxia, leading to sustained accumulation of HIF1α, downregulation of MiR‐155, and KLF4/MMP9/SMA induction.MethodsTo address this hypothesis, we measured expression of HIF1α, MiR‐155, KLF4, MMP9, and SMA in renal cortical tissue from sham, and CHF animals (n=4–8 per group) with and without ablation of the CBC (CBA). CHF was induced in rats by coronary artery ligation (CAL) and CBA was performed (4 weeks post‐CAL) by cryogenic ablation. CHF was confirmed via echocardiography under isoflurane anesthesia (1–1.5%). At 8‐weeks post‐CAL, rats were humanely euthanized and renal cortical tissue was collected and analyzed for HIF1α, KLF4, MMP9, and SMA expression via western blot and MiR‐155 expression by RT‐qPCR.ResultsEjection fraction was 72±2% in sham animals, 34±2% in CHF animals, and 32±2% in CHF‐CBA animals (p<0.05 sham vs. CHF and CHF‐CBA). Expression of HIF1α was 1.37±0.33 in CHF rats relative to sham, and 1.25±0.15 in CHF‐CBA relative to sham. KLF4 was 1.64±0.25 in CHF rats relative to sham, and this effect was attenuated in CHF‐CBA (1.06±0.16 relative to sham, p<0.05 vs. CHF). MMP9 expression in CHF rats was 1.79±0.43 relative to sham and 1.092±0.23 in CHF‐CBA relative to sham. SMA expression in CHF rats was 0.58±0.17 relative to sham and 0.83±0.15 relative to sham in CHF‐CBA. MiR‐155 expression in CHF rats was 0.48±0.11 relative to sham, and this effect was attenuated by CBA (0.73±0.12 relative to sham, p<0.05 vs. CHF).ConclusionThese results suggest a novel relationship between CBC function and expression of renal cortical MiR‐155 and KLF4 in CHF, and that CBA has the potential to influence EMT pathways in the kidney in this pathophysiological setting.Support or Funding InformationThis work was supported by a grant from NHLBI (1 R15 HL138600‐01)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Background/SignificanceSleep apnea (SA) is associated with hypertension and chronic kidney disease. Changes in adenosine signaling associated with chronic intermittent hypoxia (CIH) during apneic episodes may alter glomerular hemodynamics and contribute to hyperfiltration. In addition, increased signaling through the adenosine type 2B receptor (A2B) may promote inflammation and contribute to renal damage and eventual declines in renal function.HypothesisWe hypothesized that short‐term exposure to CIH would promote increased glomerular filtration rate and upregulation of A2B, IL‐6, NGAL, and α‐smooth muscle actin (SMA) expression in the kidney.MethodsAdult male Sprague Dawley rats were exposed to 10 days CIH (60 sec. FiO2 10%, 120 sec. FiO2 21%) for 8h/d. Glomerular filtration rate (GFR) was measured transdermally (Medibeacon) pre‐ and post‐CIH, and post‐CIH (or sham) renal blood flow (RBF) was measured using Transonic flow probes (2% isoflurane, FiO2 21% and 10%). Cortical and medullary expression of A2B, IL‐6, NGAL, and α‐smooth muscle actin (SMA) was measured via western blot.ResultsWeight‐corrected RBF decreased modestly (15%) after 10 days of CIH (1.89±0.13 mL/min/g vs. 1.42±0.16 mL/min/g, p<0.05). In contrast weight‐corrected GFR increased by 80% from pre‐ to post‐CIH measurements (3.1±0.27 mL/min/g vs. 5.5±0.51 mL/min/g, p<0.05). Renal cortical A2B (1.0±0.09 sham vs. 1.42±0.15 CIH, p<0.05) and IL‐6 (1.0±0.11 sham vs. 1.56±0.21 CIH, p<0.05) and medullary NGAL (1.0±0.22 sham vs. 2.68±0.65 CIH, p<0.05) expression was increased in CIH relative to sham tissue. SMA was not significantly different between groups.ConclusionsIntermittent hypoxia induces glomerular hyperfiltration and upregulation of renal A2B/pro‐inflammatory pathways, which in turn may precede renal injury.Support or Funding InformationSupported by a grant from NHLBI (R15 HL138600‐01 to NJM)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
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