to the editor: We want to recognize Dr. Schreuder's careful reading of our manuscript, as well as the due diligence in assessing the references. Overall, we strongly believe that neither one mechanism nor one animal model will completely encompass the mechanisms through which perinatal events lead to human renal pathophysiology. The human condition extends across a spectrum of environments and genotypes. To narrow an approach of a translationally relevant question to a single paradigm is “naïve reductionism” at its worst. Indeed, in this manuscript, we make the statement that “… a single mechanism responsible for abnormal kidney development is unlikely…” We are grateful for the insights that we have gleaned from our scientific colleagues, such as Dr. Alexander and her group at the University of Mississippi.
Specifically, Dr. Schreuder raises concerns about the effect of the postnatal diet and references the manuscript of Dr. Wlodek (3). Two notable differences exist between our studies and Dr. Wlodek's study. The first is our use of Sprague-Dawley rats vs. Dr. Wlodek's use of Wistar rats. As many investigators have noted in the transgenic literature, individual strains often responded differently to similar interventions. The second difference is that Dr. Wlodek's group ligates both the uterine artery and vein, whereas we ligate only the uterine arteries. These differences are important because, as referenced in methods of our manuscript, we have previously demonstrated that lactation and breast milk from intrauterine growth-restricted (IUGR) dams did not differ from control dams (2). This was published in 2006. Furthermore, since we are unlikely to convince human mothers of IUGR infants to subscribe to cross-fostering, the relevance of doing so is minimal.
Another concern that Dr. Schreuder raises is the random culling of our litters. First, Dr. Schreuder is concerned about our culling the litter number to six, which has been a consistent practice in our group for the last 10 years. Because of the issues Dr. Schreuder raises upon milk quantity and quality, to alter this number would insert another variable between our earlier studies and our most recent work. This would moderate the ability of our group, as well as our scientific colleagues, to appropriately assess the relevance of newer findings compared with the original baseline characterization of our model. It is also important to note that Dr. Wlodek's group culls their litters to five, and that Dr. Alexander's group culls their litters to eight. Six is a reasonable number.
Second, we randomly cull our litters to ameliorate previously raised concerns of biasing our samples. We recognize that both of these issues may lend to confusion when assessing different models, but the important point is that most groups are using a consistent litter number to minimize the variability, which may occur secondary to milk quantity and/or quality within their own studies. Dr. Schreuder does point out that the influence of the postnatal environment upon our results cannot be determined. Our study was not designed to do this a priori and to do so post hoc would be of minimal significance.
Dr. Schreuder is correct in that understanding the nature of the insult is important to further our understanding of renal programming. However, we suggest that the most relevant details involve the fetal metabolic and endocrinological environment, as well as the fetal molecular milieu, as opposed to the position of the pup within the uterus. A bicornuate uterus and gestation of 10 offspring is relatively rare in the human. As a result, we have focused upon the molecular pathways involved in steroid signaling and metabolism, particularly considering our previous finding of elevated corticosterone levels in the 1-day-old IUGR rat pup (1). As detailed in our manuscript, our findings of altered renal 11β-hydroxysteroid dehydrogenase type 2 and cyclooxygenase-2 expression are relevant, based upon previous observations in humans and animal models of increased antenatal glucocorticoid levels.
The finding of increased corticosterone is important considering Dr. Schreuder's next concern, which is the tail cuff method. He is correct that the ideal method would be to use telemetry, a technique in which Dr. Schreuder's owns expertise. However, the concerns raised in his letter to the editor are already acknowledged within the manuscript: “A limitation of our study is that with the tail cuff method we cannot differentiate whether the variation in blood pressures found between controls and IUGR animals could be due to an exaggerated stress response vs. baseline blood pressures. Moreover, in this study, we cannot establish whether the elevated blood pressures observed in the IUGR group are secondary to a renal or a hypothalamic-pituitary-adrenal axis effect.”
Finally, the strength and focus of our research group are the molecular consequences of intrauterine growth retardation. Others are more capable of describing the adult rat phenotypic response to IUGR. In that sense, we are excited about the complimentary investigations that will be instigated by these studies, whether it is by us or others, and we look forward to interacting and collaborating with our colleagues who have similar interests.
- Copyright © 2007 the American Physiological Society