Renal biomarkers of acute kidney injury in response to increasing intermittent hypoxia episodes in the neonatal rat

Abstract

Background 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. Methods At 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). Results Histopathology 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. Conclusions Chronic 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.

Educational Review: The Impact of Perinatal Oxidative Stress on the Developing Kidney

“…In the developing kidney, the negative impact of oxidative stress related to fluctuating oxygen exposure from hyperoxia to intermittent hypoxia, has also been implicated in the development of kidney injury in postnatal animal models (60,(73)(74)(75)(76)(77)(78) (Table 1). Nephrogenesis is complete by the 36th week of gestation in humans, but it continues until approximately postnatal day 10-14 in rats (73).…”

Hypoxia-Induced Kidney Injury in Newborn Rats

“…Although hypoxia is one of the most common causes of acute and chronic kidney injury, the precise mechanisms of hypoxia-induced kidney injury remain poorly understood [ 19 ]. Zangaladze et al’s study mimicked neonatal intermittent hypoxia after birth and found kidney damage with associated elevations of vasoconstrictors [ 20 ], and Plotnikov et al explored acute kidney injury with severe hypoxia (8% O 2 ) for 2 h in the neonatal rat [ 15 ]. Differently from those two studies, our study focused on persistent, not intermittent, neonatal hypoxia mimicking clinical condition, such as congenital heart disease or bronchopulmonary dysplasia, and further investigated the effects and molecular mechanism of kidney injury.…”

Determinación De La Cistatina C Como Marcador Precoz En Detección De La Insuficiencia Renal En Latinoamérica

“…Este es el caso de la cistatina C, una proteína de bajo peso molecular propuesta como marcador de función renal más sensible que la creatinina al detectar de forma precoz alteraciones en la función renal. De hecho, la cistatina C no se modifica por los factores que afectan las concentraciones de la creatinina sérica (Zangaladze, Cai, Marcelino, & Aranda, 2021).…”