Offspring’s hydromineral adaptive responses to maternal undernutrition during lactation P. Nuñez*, J. Arguelles and C. Perillan Departamento de Biologia Funcional (Area de Fisiologia), Facultad de Medicina, Universidad de Oviedo, Oviedo, Spain Early development, throughout gestation and lactation, represents a period of extreme vulnerability during which susceptibility to later metabolic and cardiovascular injuries increases. Maternal diet is a major determinant of the foetal and newborn developmental environment; maternal undernutrition may result in adaptive responses leading to structural and molecular alterations in various organs and tissues, such as the brain and kidney. New nephron anlages appear in the renal cortex up to postnatal day 4 and the last anlages to be formed develop into functional nephrons by postnatal day 10 in rodents. We used a model of undernutrition in rat dams that were food-restricted during the first half of the lactation period in order to study the long-term effects of maternal diet on renal development, behaviour and neural hydromineral control mechanisms. The study showed that after 40% food restriction in maternal dietary intake, the dipsogenic responses for both water and salt intake were not altered; Fos expression in brain areas investigated involved in hydromineral homeostasis control was always higher in the offspring in response to isoproterenol. This was accompanied by normal plasma osmolality changes and typical renal histology. These results suggest that the mechanisms for the control of hydromineral balance were unaffected in the offspring of these 40% food-restricted mothers. Undernutrition of the pups may not be as drastic as suggested by dams’ restriction. Received 14 April 2015; Revised 7 July 2015; Accepted 10 July 2015; First published online 3 August 2015 Key words: early programming, Fos-ir cells, dipsogenic behavior, lactation period, maternal undernutrition Introduction Adverse prenatal environmental conditions are known to induce permanent adaptive changes in the developing foetus that may promote short-term survival but may increase vulnerability to metabolic and cardiovascular injuries. These processes, accord- ing to the developmental origins of adult disease hypothesis, 1–3 constitute intrauterine programming that can result in adult disease that originated in utero. Moderate reduction in food intake has well-known systemic consequences, including weight loss and a decrease in fat mass. 4,5 Diet restriction of 40% was associated with significantly increased corticosterone con- centrations and led to significant reductions in the amount of serum thyroid-stimulating hormone, leptin, metabolic rate and body mass. 6,7 Studies supporting this intrauterine programming hypothesis have demonstrated that adverse foetal or neonatal environmental conditions such as undernutrition result in adaptive responses leading to structural and molecular altera- tions in various organs and tissues. 8–11 Different experimental models have shown a decrease in the number of nephrons in the offspring after maternal under- nutrition throughout pregnancy in the rat. 12–16 But the postnatal period is also crucial in determining the final nephron number; as a recent study has demonstrated a normal lactation environment could even repair the effect of intrauterine growth restriction on nephron number. 14 In the rat, <20% of nephrons are formed at birth; nephrogenesis is known to continue up to postnatal day 10, when the remaining 80% of nephrons are formed. 17,18 One study 19 described a model of postnatal food restriction in the rat in which litter size is increased to 20 pups, which leads to growth restriction, produced a 25% reduction in nephron number. Maternal protein restriction throughout lactation has also pro- duced a significant deficit in nephron number in the offspring in early postnatal and adult life, with a decrease in renal function and changes in plasma protein concentrations. 11–20 Kidney has important functions in the renin–angiotensin–aldosterone system (RAAS). The physiological importance of RAAS is the compen- sation of hypovolemia and hyponatremia, so it is a key regulator of fluid homeostasis. For instance, there is accumulated evidence supporting the hypothesis that altered development as a con- sequence of environmental insult, as could be kidney alterations, may affect the ‘programming’ of hypertension later in life. 21,22 Numerous reports have demonstrated that some brain areas, together with the kidneys, play a critical role in the control of water and salt intake, as well as body fluid homeostasis. 23 In the central nervous system, the lamina terminalis including the subfornical organ (SFO), along with some hypothalamic nuclei have Angiotensin II (Ang II) receptors. 24 Immunocytochemical labelling of the protein product of the c-fos gene, Fos protein, has been used as a marker of cellular activation in neuro- endocrine systems. 24–26 Many studies have documented the effects of hyperosmolality, hypovolaemia or Ang II on Fos expression in the rat brain. In particular, a relatively large number of studies has reported induction of Fos expression in *Address for correspondence: P. Nuñez, Departamento de Biologia Funcional (Area de Fisiologia), Facultad de Medicina, Universidad de Oviedo, C/Julian Claveria 6, E-33006 Oviedo, Spain. (Email nunezpaula@uniovi.es) Journal of Developmental Origins of Health and Disease (2015), 6(6), 520–529. © Cambridge University Press and the International Society for Developmental Origins of Health and Disease 2015 ORIGINAL ARTICLE doi:10.1017/S204017441500135X