Septic acute kidney injury (AKI) and myocardial dysfunction are leading causes of mortality with no accepted method of therapy. In this study we demonstrate the role of growth differentiating factor 15 (GDF15) in septic AKI and myocardial dysfunction using a murine lipopolysaccharide (LPS)-induced sepsis model and an in vitro cell culture system. Data show that GDF15 deficiency augments inflammatory response and exacerbates renal and cardiac injury induced by LPS, while over-expression of GDF15 protects the kidney and heart from LPS-induced organ dysfunction. Therefore, this study highlights the therapeutic potential of GDF15 in the treatment of endotoxin-induced sepsis.

No abstract

Phoenixin (PNX) is a newly identified reproductive peptide required for the estrous cycle. It is most highly expressed in the hypothalamus, where it is a positive regulator of gonadotropin-releasing hormone (GnRH) and kisspeptin. However, it is unknown what signals lie upstream of Pnx to coordinate its effects on GnRH and kisspeptin. We investigated the effects of the hormones, estrogen and leptin; the fatty acids, palmitate, docosahexaenoic acid (DHA), oleate and palmitoleate; and the endocrine disrupting chemical BPA on Pnx mRNA levels. We also examined whether the signaling pathways of nitric oxide, lipopolysaccharide, cAMP and protein kinase C could alter Pnx expression. Immortalized hypothalamic neurons were treated from 2 to 24 h with these compounds and Pnx mRNA levels were measured with RT-qPCR. Unexpectedly, only BPA as well as the fatty acids, palmitate, DHA and oleate, could alter Pnx expression; therefore suggesting that Pnx may fulfill a nutrient-sensing role in the hypothalamus. Our study is the first to delineate potential regulators of this novel neuropeptide, and our findings provide some insight into the functional role of PNX in the hypothalamus.

No abstract

Bisphenol A (BPA), a ubiquitous endocrine-disrupting chemical, interferes with reproduction and is also considered an obesogen. The neuropeptide Y (NPY) neurons of the hypothalamus control both food intake and reproduction and have emerged as potential targets of BPA. These functionally diverse subpopulations of NPY neurons are differentially regulated by peripheral signals, such as estrogen and leptin. Whether BPA also differentially alters Npy expression in subpopulations of NPY neurons, contributing to BPA-induced endocrine dysfunction is unclear. We investigated the response of six immortalized hypothalamic NPY-expressing cell lines to BPA treatment. BPA upregulated Npy mRNA expression in four cell lines (mHypoA-59, mHypoE-41, mHypoA-2/12, mHypoE-42), and downregulated Npy in two lines (mHypoE-46, mHypoE-44). This differential expression of Npy occurred concurrently with differential expression of estrogen receptor mRNA levels. Inhibition of GPR30 or ERβ prevented the BPA-mediated decrease in Npy, wherease inhibition of energy sensor 5’ adenosine monophosphate-activated protein kinase (AMPK) with compound C prevented BPA-induced increase in Npy. BPA also altered neuroinflammatory and oxidative stress markers in both mHypoA-59 and mHypoE-46 cell lines despite the differential regulation of Npy. Remarkably, treatment with BPA in an antioxidant-rich media, neurobasal A (NBA), or with ROS scavenger tauroursodeoxycholic acid (TUDCA) mitigated the BPA-induced increase and decrease in Npy. Furthermore, two anti-oxidant species from NBA, N-acetylcysteine and vitamin B6, diminished the induction of Npy in the mHypoA-59 cells, demonstrating these supplements can counteract BPA-induced dysregulation in certain subpopulations. Overall, these results illustrate the differential regulation of Npy by BPA in neuronal subpopulations, and point to oxidative stress as a pathway that can be targeted to block BPA-induced Npy dysregulation in hypothalamic neurons.