Neonatal hydronephrosis induced by TCDD exposure

Neonatal hydronephrosis induced by TCDD exposure via lactation has a critical window for onset: the incidence of this disease peaks around PNDs 1–4, followed by a rapid decrease to a substantially null level in adulthood (Couture-Haws et al., 1991; Yoshioka et al., 2016). The EP1 protein was localized in the intramedullary collecting ducts in neonatal kidneys (Fig. 6), and it was found to be abundant in the neonatal period, followed by a decrease after weaning in rats (Brennan et al., 2008). In addition, TCDD exposure did not result in a significant change in urinary PGE2 concentrations between 14-day-old EP1+/+ and EP1–/– mice (Fig. 5A). These lines of evidence support the notion that increased PGE2 concentration due to TCDD exposure exerts an effect via EP1 and that regulation of EP1 concentration in the developing kidney may explain the critical window for hydronephrosis onset. The next intriguing question is how EP1 is relevant to TCDD-induced reduction in urine concentration ability, characterized by polyuria in the neonatal period. It is logically possible to postulate the involvement of sodium ion transport and/or arginine vasopressin (AVP)-mediated aquaporin-2 (AQP2) trafficking in the medullary collecting ducts. The first possibility is that increased quantities of PGE2 by TCDD bind to EP1 in the epithelial cells of the medullary collecting ducts, inhibit the epithelial sodium transporter (ENaC) in the medullary collecting ducts, and then enhance urine formation. A PGE2/ EP1-dependent increase in the intracellular calcium concentration was shown to mediate the suppression of sodium 5-Carboxymethylester-UTP in the medullary collecting ducts (Guan et al., 1998; Hebert et al., 1991; Pearce et al., 2015; Stokes and Kokko, 1977). Besides, studies have shown that sodium reabsorption plays a key role in urine concentrating ability on PNDs 1 − 7 (Edwards BR and LaRochelle, 1981; Liu et al., 2001) and that ENaC abundance drastically increases on PNDs 1 − 3 and decreases after PND 14 (Vehaskari et al., 1998). These results suggest the presence of a critical window common for urine concentrating ability by ENaC and susceptibility to TCDD-induced hydronephrosis in the neonatal period. The second possibility is that deregulation of AQP2 by TCDD may disrupt water reabsorption in the medullary collecting ducts. Under normal conditions, AVP (also called antidiuretic hormone) released from the pituitary gland activates the translocation of AQP2 from intracellular vesicles to the apical cell membrane in the principal cells of the medullary collecting ducts, and AQP2 is involved in the urine concentrating ability of the kidneys (Moeller et al., 2011; Pearce et al., 2015; Rojek et al., 2006). An increase in PGE2 suppresses AVP-activated AQP2 translocation (Hebert et al., 1993; Tamma et al., 2003; Zelenina et al., 2000), leading to the disruption of water reabsorption in the medullary collecting ducts. However, our recent study showed that secretion of AVP from the pituitary gland is not affected by TCDD treatment, but that total AQP2 protein amounts are significantly reduced in TCDD-exposed kidneys on PND 14 (Yoshioka et al., 2016). It is, therefore, conceivable that the interference of AQP2 trafficking by an increase in PGE2 concentration may decrease water permeability at the collecting ducts and produce polyuria (Yoshioka et al., 2016). We showed that urine osmolality does not decrease in TCDD-exposed EP1–/– pups, although PGE2 production increases in this group (Fig. 5A,B). This result suggested that TCDD-induced neonatal hydronephrosis is caused by defect of urine concentrating ability via PGE2/ EP1, and that PGE2 production is not affected by EP1 existence. Although EP1 activation increases the abundance of phosphorylated nuclear factor kappa B (NFkB) and cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB) (Ji et al., 2012), it is not clearly understood how downstream signaling beyond EP1 can be associated with downregulation of AQP2 and AQP2 trafficking to the apical membrane in renal the collecting ducts. Whether the pathogenesis of TCDD-induced neonatal hydronephrosis occurs via either of the two possible mechanisms or both in combination remains to be explored.