Chronic Intermittent Hypoxia is Associated with Sustained Reduction in Renal Blood Flow and Downregulation of Renal KLF2

Abstract

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.