Am J Physiol Renal Physiol. 2017 Oct 1;313(4):F864-F873. doi: 10.1152/ajprenal.00538.2016.

Tubuloglomerular feedback responses in offspring of dexamethasone-treated ewes.

Turner AJ1,2, Brown RD2,3, Brandon AE2, Persson AEG2,3, Gibson KJ2.

1 Faculty of Medicine and Health Sciences, Macquarie University, Sydney, Australia;
2 Department of Physiology, School of Medical Sciences, University of New South Wales, Sydney, Australia; and.
3 Division of Integrative Physiology, Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden.


Via developmental programming, prenatal perturbations, such as exposure to glucocorticoids and maternal malnutrition alter kidney development and contribute to the development of hypertension. To examine the possibility that alterations in tubuloglomerular feedback (TGF) contribute to the development of hypertension in offspring following maternal dexamethasone treatment (Dex) in early gestation, studies were conducted in fetal sheep and lambs. Pregnant ewes were infused with dexamethasone (0.48 mg/h) at 26-28 days gestation. No differences were observed in mean arterial pressure, glomerular filtration rate. or electrolyte excretion rates between the Dex and Untreated fetuses or lambs. Gestational exposure to Dex markedly enhanced TGF sensitivity, as the turning point in Dex-treated fetuses was significantly lower (12.9 ± 0.9 nl/min; P < 0.05) compared with Untreated fetuses (17.0 ± 1.0 nl/min). This resetting of TGF sensitivity persisted after birth (P < 0.01). TGF reactivity did not differ between the groups in fetuses or lambs. In response to nitric oxide inhibition, TGF sensitivity increased (the turning point decreased) and reactivity increased in Untreated fetuses and lambs, but these effects were blunted in the Dex-treated fetuses and lambs. Our data suggest that an altered TGF response may be an underlying renal mechanism contributing to the development of hypertension in the Dex model of fetal programming. The lower tonic level of NO production in these dexamethasone-exposed offspring may contribute to the development of hypertension as adults.



It is known that events that occur during fetal life may have lasting effects on the adult and may in fact predispose to the development of adult disease such as hypertension (Barker 2004). The study described in this paper investigates the developmental origins of hypertension.


The prevalence of hypertension in Australia is >25% so studies which contribute to our understanding of mechanisms by which hypertension might be programmed have major health significance. A reduced number of nephrons (filtering units in the kidney) has been shown, in many cases, to lead to hypertension and renal disease (Brenner, Garcia et al. 1988, Hinchliffe, Lynch et al. 1992, Manalich, Reyes et al. 2000, Keller, Zimmer et al. 2003, Reyes and Manalich 2005).


We examine the tubuloglomerular feedback (TGF) system in the kidney during normal development and in an animal model which has been shown to affect fetal kidney development, predisposing the fetus to the development of hypertension later in life.


TGF is one of the mechanisms the kidney uses to regulate glomerular filtration rate whereby the rate of fluid delivery to the distal nephron influences the rate of glomerular filtration. It is a negative feedback loop which acts on the single nephron. When the rate of fluid delivery to the distal nephron increases this is detected by specialized cells in the macula densa, and TGF causes single nephron glomerular filtration rate (SNGFR) to fall. Conversely, detection of a decreased distal delivery of fluid results in an increase in SNGFR. The TGF system is essential for the maintenance of fluid and electrolyte homeostasis and disturbance of this mechanism has been implicated in the development of hypertension (Boberg and Persson 1986, Persson 1988).


Studies have found that the sensitivity of this TGF system is increased in hypertensive rat strains that are genetically predisposed to hypertension before they become hypertensive. We wanted to find out if an abnormal resetting of the TGF system may also play a part in the development of hypertension resulting from prenatal programming with steroids.


Pregnant sheep were treated with a low dose of Dexamethasone (Dex) at a very early stage of gestation (26-28 days of gestation, term = 150 days in the sheep). 26 – 28 days of gestation in the sheep is the critical period of fetal development when the nephrons are being formed in the fetal kidneys. Dex treatment results in offspring that have a lower number of nephrons compared to untreated animals and have been shown to develop hypertension in adulthood due to the resultant alteration in kidney function. Humans with a reduced nephron number may also be more prone to developing hypertension (Brenner and Mackenzie 1997).


One reason for using sheep in this study was that, like the human, the sheep completes nephrogenesis before birth. In the rat, the development of the kidney continues for 7 – 10 days after birth, during which time there is the opportunity to replenish the nephron complement (if nephrogenesis has been affected during fetal development) after maternal and placental constraints have been eliminated. (See Table 1).


Table 1: Comparison of periods of nephrogenesis.

Nephrogenesis complete % gestation Term
Humans 35 weeks gestation 88 280 days
Sheep 130 days gestation 87 150 days
Rats 7 – 10 postnatal days 130 – 143 23 days



The experiments described in this paper examine TGF responses in late gestation sheep fetuses (134 – 141 days of gestation) and in 1 – 3 week old lambs which had been exposed to maternal Dex in early gestation. Our hypothesis was that TGF dysfunction would be present before these animals developed hypertension.


We also investigated the effect of inhibition of nitric oxide (NO) production on the TGF system in these animals. NO is a major regulator of glomerular haemodynamics, tubular transport and TGF responses.


The data presented here, suggest a major role for differences in TGF responsiveness as a cause of hypertension in dexamethasone treated offspring. They also indicate that the lower tonic level of NO production in these dexamethasone exposed offspring may contribute to the development of hypertension as adults.



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