Peripheral Chemoreceptor Ablation Modulates Renal MiR‐155/KLF4 Expression in Chronic Heart Failure

Abstract

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.