Loss of<i>miR-17~92</i>results in dysregulation of<i>Cftr</i>in nephron progenitors

Abstract

We have previously demonstrated that loss of <i>miR-17~92</i> in nephron progenitors in a mouse model results in renal hypodysplasia and chronic kidney disease. Clinically, decreased congenital nephron endowment because of renal hypodysplasia is associated with an increased risk of hypertension and chronic kidney disease, and this is at least partly dependent on the self-renewal of nephron progenitors. Here, we present evidence for a novel molecular mechanism regulating the self-renewal of nephron progenitors and congenital nephron endowment by the highly conserved <i>miR-17~92</i> cluster. Whole transcriptome sequencing revealed that nephron progenitors lacking this cluster demonstrated increased <i>Cftr</i> expression. We showed that one member of the cluster, <i>miR-19b</i>, is sufficient to repress <i>Cftr</i> expression in vitro and that perturbation of Cftr activity in nephron progenitors results in impaired proliferation. Together, these data suggest that <i>miR-19b</i> regulates <i>Cftr</i> expression in nephron progenitors, with this interaction playing a role in appropriate nephron progenitor self-renewal during kidney development to generate normal nephron endowment.