Low nephron number increases an individual?s risk for developing hypertension and chronic kidney disease, which affect approximately 30% and 15% of American adults, respectively. Individuals with decreased nephron number are more sensitive to the detrimental effects that high salt and high fat diets have on kidney health. Nephron number is largely determined before birth in humans by the balance between self-renewal and differentiation of nephron progenitors (cells which differentiate to form the majority of the nephron). This balance is influenced, in part, by signals from the branching ureteric bud (cells that form the collecting ducts) that induce nephrons. Spatially, nephron progenitors surround ureteric bud tips and reside in the nephrogenic zone, which is a physiologically hypoxic environment. Recently, it has been shown that increased blood flow and oxygen delivery to this nephrogenic zone is associated with nephron progenitor differentiation are associated with their differentiation, but the mechanisms underlying how hypoxia may regulate nephrogenesis are unknown. My preliminary data demonstrates that microRNA-210 (miR-210) is a hypoxia-regulated microRNA (miRNA) that is expressed in nephron progenitors during kidney development, and that a global miR-210 knockout results in significantly reduced nephron number (~45% decrease). miRNAs are ~22nt small noncoding RNAs that fine- tune gene expression through post-transcriptional regulation of specific target mRNAs and are essential for proper mammalian development. miR-210 is the most consistently induced miRNA in hypoxia and is directly regulated by the Hypoxia Inducible Factor (HIF) transcription factor family. In turn, miR-210 regulates metabolism, apoptosis, cell cycle progression, and angiogenesis, all of which are tightly regulated in nephron progenitors. Recently published chromatin immunoprecipitation-sequencing data suggests that miR-210 may also be regulated by the nephron progenitor-specific transcription factor Six2. Furthermore, my preliminary data show that the miR-210 knockout kidneys have overexpression of Six2 and ?-catenin, both of which are predicted to promote early differentiation of nephron progenitors. Interestingly, miR-210 knockout kidneys have ~45% reduction in nephron number. Together, these data suggest miR-210 plays a role in regulating the balance between self-renewal and differentiation of nephron progenitors. My project will 1) determine the kidney developmental phenotype of the miR-210 knockout mouse and its response to diet-induced stress; and 2) investigate the downstream targets of miR-210 in nephron progenitors. Overall, my project will be the first to define how miR-210 regulates nephron progenitor behavior during kidney development to dictate nephron formation and function.
Hypertension and kidney disease are highly prevalent in both children and adults and significantly impact human health. Abnormal kidney development increases the risk for developing these diseases, however their etiology is poorly understood. This study will investigate how hypoxia-controlled microRNA-210 regulates kidney development and function.
