The effect of periconceptional alcohol exposure on renal and cardiovascular development and function

Abstract

Alcohol consumption in Australia is high and despite the NHMRC guidelines clearly indicating that when pregnant or planning a pregnancy, not drinking is the safest option, many women unknowingly consume alcohol prior to pregnancy recognition. Research using animal models has linked alcohol exposure at various times and doses (particularly high) throughout pregnancy with alterations in offspring behaviour and to a lesser extent, impairments to renal and cardiac development and function. Therefore, it is the aim of this PhD thesis to examine if periconceptional alcohol affects the development and disease progression of the kidney and heart. A further aim was to examine if any deleterious outcomes are exacerbated by the consumption of a high fat diet. Outbred female Sprague Dawley rats consumed a liquid diet of 12.5%v/v ethanol (PC:EtOH) or a control diet from four days before mating until four days after mating. Rats were then returned to standard lab chow and dams killed for tissue collections during fetal life (E20) or allowed to litter down naturally. At postnatal day 30 (PN30) nephron number was determined. A subset of offspring were fed a diet high in fat and cholesterol (HFD) from 3 months of age. Rats were housed in metabolic cages for 24 hr to assess renal function at 6, 12 and 19 months of age. Blood pressure (by radiotelemetry), heart function (in vivo using echocardiography and ex vivo using Langendorff preparation), and vascular reactivity were assessed in offspring. Kidneys, hearts and brain regions were collected for mRNA and protein analysis at 19 months of age. PC:EtOH slowed kidney growth and decreased nephron endowment at postnatal day 30, particularly in male offspring. While urine flow was altered by PC:EtOH early in life, by 19 months of age females exposed to alcohol exhibited an increased urine flow rate when compared to control animals. Arginine vasopressin (AVP) levels were not altered following PC:EtOH both during hydrated and dehydrated conditions. Despite decreased nephron number and altered urine flow, PC:EtOH did not alter offspring blood pressure. Surprisingly, PC:EtOH resulted in increased mRNA expression of arginine vasopressin receptor 2 and mRNA and protein expression of aquaporin-2 (AQP2). Immunohistochemistry demonstrated altered cellular localisation following PC:EtOH suggesting AQP2 was not appropriately inserted into Financial support