Poster abstracts
Poster number 51 submitted by Shelby Hemker
Hypoxic induction of c-Myc and microRNAs to inhibit nephron progenitor differentiation
Shelby L. Hemker (Pediatrics, University of Pittsburgh), Andrew Clugston (Pediatrics, University of Pittsburgh; Developmental Biology, University of Pittsburgh), Dennis Kostka (Developmental Biology, University of Pittsburgh), Sunder Sims-Lucas (Pediatrics, University of Pittsburgh), Jacqueline Ho (Pediatrics, University of Pittsburgh)
Abstract:
Placental insufficiency causes fetal hypoxia, reduced blood flow to the kidneys, and is the main cause of intrauterine growth restriction (IUGR). IUGR and fetal hypoxia adversely affect kidney development, resulting in congenital anomalies of the kidney and urinary tract (CAKUT), the leading cause of renal failure in children. We propose that oxygen tension in the developing kidney is precisely controlled to facilitate the normal development of nephrons, the functional unit of the kidney. To investigate how different oxygen levels alter gene expression of the developing kidney, we transcriptionally profiled embryonic day 12.5 mouse kidneys cultured in either 1%, 5%, or 21% O2. As expected, the Hypoxia Inducible Factor (HIF) transcriptional network—which regulates the expression of many genes in response to cellular hypoxia—was up-regulated in the kidneys cultured in 1% O2. Furthermore, there is increased expression of early kidney development markers and decreased expression of genes expressed by maturing kidney epithelial cells in the 1% O2 kidney cultures, suggesting an impairment in differentiation. This was associated with evidence for increased activity of the c-Myc pathway, which is known to be an important regulator of proliferation in nephron progenitor cells. Finally, several hypoxia-responsive microRNAs were demonstrated to be differentially expressed, and Ingenuity Pathways Analysis was used to predict differentially expressed miRNA-mRNA target pairs in hypoxia. Together, this data suggests that c-Myc and microRNAs are important HIF effectors that inhibit nephron progenitor differentiation in kidney development, in response to varying oxygen tension.
Keywords: microRNA, RNA sequencing, kidney development