Abstract
BackgroundWe tested the hypotheses that: 1) early exposure to increasing episodes of clinically relevant intermittent hypoxia (IH) is detrimental to the developing kidneys; and 2) there is a critical number of daily IH episodes which will result in irreparable renal damage that may involve angiotensin (Ang) II and endothelin (ET)-1.MethodsAt birth (P0), neonatal rat pups were exposed to brief IH episodes from the first day of life (P0) to P7 or from P0-P14. Pups were either euthanized immediately or placed in room air (RA) until P21. RA littermates served as controls. Kidneys were harvested at P7, P14, and P21 for histopathology; angiotensin converting enzyme (ACE), ACE-2, ET-1, big ET-1, and malondialdehyde (MDA) levels; immunoreactivity of ACE, ACE-2, ET-1, ET-2, ET receptors (ETAR, ETBR), and hypoxia inducible factor (HIF)1α; and apoptosis (TUNEL stain).ResultsHistopathology showed increased renal damage with 8–12 IH episodes/day, and was associated with Ang II, ACE, HIF1α, and apoptosis. ACE-2 was not expressed at P7, and minimally increased at P14. However, a robust ACE-2 response was seen during recovery with maximum levels noted in the groups recovering from 8 IH episodes/day. ET-1, big ET-1, ETAR, ETBR, and MDA increased with increasing levels of neonatal IH.ConclusionsChronic neonatal IH causes severe damage to the developing kidney with associated elevations in vasoconstrictors, suggesting hypertension, particularly with 8 neonatal IH episodes. ACE-2 is not activated in early postnatal life, and this may contribute to IH-induced vasoconstriction. Therapeutic targeting of ACE and ET-1 may help decrease the risk for kidney injury in the developing neonate to prevent and/or treat neonatal acute kidney injury and/or chronic kidney disease.
Highlights
Hypoxemic respiratory failure requiring mechanical ventilation occurs in approximately 18 per 1000 live births [1], and is associated with increased risk of mortality and morbidity [2]
At Postnatal day 21 (P21) following 7 days of intermittent hypoxia (IH) and recovery in room air (RA) for 14 days (P21– 7DO2), mean kidney weights increased in the hyperoxia and 4 IH groups
Mean kidney weights in all the oxygen groups were comparable at Postnatal day 14 (P14) compared to RA
Summary
Hypoxemic respiratory failure requiring mechanical ventilation occurs in approximately 18 per 1000 live births [1], and is associated with increased risk of mortality and morbidity [2]. Studies comparing the tissues of kidneys from preterm neonates to term controls found that renal maturation accelerated after preterm birth, with an increased number of glomerular generations [12]. Compared with gestational controls, preterm kidneys had a greater percentage of morphologically abnormal glomeruli and a significantly larger cross-sectional area of the renal corpuscle, suggestive of renal hyperfiltration [12]. These observations suggested that the preterm kidney may have fewer functional nephrons increasing the vulnerability to impaired renal function in both the early postnatal period and later in life. We tested the hypotheses that: 1) early exposure to increasing episodes of clinically relevant intermittent hypoxia (IH) is detrimental to the developing kidneys; and 2) there is a critical number of daily IH episodes which will result in irreparable renal damage that may involve angiotensin (Ang) II and endothelin (ET)-1
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