Prolonged prenatal hypoxia selectively disrupts collecting duct patterning and postnatal function in male mouse offspring

Abstract

Prenatal hypoxia is a common perturbation to arise during pregnancy, and can lead to adverse health outcomes in later life. The long-lasting impact of prenatal hypoxia on postnatal kidney development and maturation of the renal tubules, particularly the collecting duct system, is relatively unknown. In the present study, we used a model of moderate chronic maternal hypoxia throughout late gestation (12% O exposure from embryonic day 14.5 until birth). Histological analyses revealed marked changes in the tubular architecture of male hypoxia-exposed neonates as early as postnatal day 7, with disrupted medullary development and altered expression of Ctnnb1 and Crabp2 (encoding a retinoic acid binding protein). Kidneys of the RARElacZ line offspring exposed to hypoxia showed reduced β-galactosidase activity, indicating reduced retinoic acid-directed transcriptional activation. Wild-type male mice exposed to hypoxia had an early decline in urine concentrating capacity, evident at 4 months of age. At 12 months of age, hypoxia-exposed male mice displayed a compromised response to a water deprivation challenge, which was was correlated with an altered cellular composition of the collecting duct and diminished expression of aquaporin 2. There were no differences in the tubular structures or urine concentrating capacity between the control and hypoxia-exposed female offspring at any age. The findings of the present study suggest that prenatal hypoxia selectively disrupts collecting duct patterning through altered Wnt/β-catenin and retinoic acid signalling and this results in impaired function in male mouse offspring in later life.

Developmental programming of renal function: nephron endowment and beyond

“…In this issue of The Journal of Physiology , Walton et al . () show that the programming of kidney function by hypoxia is more complex than previously thought. In a previous study, the authors reported that prenatal hypoxia in rats causes reductions in nephron endowment in male, but not female offspring, leading to eventual glomerulosclerosis and other markers of chronic kidney disease (Walton et al .…”

“…In this follow‐up study, the authors show that male offspring exhibit altered collecting duct cellular make‐up concomitant with decreased urine concentrating ability (Walton et al . ). Although the decrease in principal cell (AQP2‐positive) content in the collecting duct could ultimately reflect a reduction in nephron endowment in programmed offspring, the functional changes in sodium concentrating ability under both normal and water‐deprivation conditions suggest this may be attributed to qualitative differences in collecting duct structure and function, rather than nephron numbers per se .…”

“…implicates reduced retinoic acid (RA) signalling as a mediator of abnormal kidney development (Walton et al . ). RA, a bioactive derivative of vitamin A, regulates ureteric bud branching and tubule segmentation in the developing kidney, and thereby plays a critical role in establishing both nephron number and cellular make‐up (Das et al .…”

Prenatal hypoxia increases susceptibility to kidney injury

“…Intrauterine hypoxia leading to prenatal hypoxia of the fetus is a common gestational stressor that can lead to a range of developmental abnormalities [1][2][3][4]. When prenatal hypoxia occurs, the developing fetus exhibits a preferential redirection of blood flow, including oxygen and nutrient supply, to the brain and heart over less vital organs such as the kidney [5,6].…”

“…Maternal chronic prenatal hypoxia of less than 10% oxygen has been shown to lead to physical and structural abnormalities [1,6,18,19]. In one study, pregnant dams with a CD1 background housed in 12% O 2 from E14.5 to P1 found that female offspring were unaffected, however male offspring exhibited decreased body weight, decreased kidney weight, and alterations in tubular development and in the corticomedullary ratio [3]. To our knowledge few studies have used 12% O 2 conditions and the present investigation is the first to characterize a secondary injury phenotype.…”