Renal dysplasia/hypoplasia is a leading cause of renal failure in children, leading to significant morbidity and mortality associated with transplan and dialysis. The risk of chronic kidney disease is linked to decreased renal reserve as a result of the formation of fewer and/or abnormal nephrons during kidney development. While much is known about the genetic control of nephron development, very little is known about the role of microRNAs (miRNAs), small, non-coding RNA molecules that negatively regulate gene expression. Our laboratory has data demonstrating that the miR-17~92 miRNA cluster is crucial to regulating nephron number and formation. Conditional loss of miR-17~92 in nephron progenitors results in renal hypodysplasia, glomerular injury and renal dysfunction in adult mice. Moreover, we observe an intermediate phenotype in animals with heterozygous loss of miR-17~92 in nephron progenitors, suggesting that the gene dosage of miR- 17~92 is key. Heterozygous mutations in the orthologous human gene (MIR17HG) results in the first known developmental defects associated with a miRNA mutation in humans, including renal anomalies. We hypothesize that loss of the miR-17~92 cluster in nephron progenitors results in an intrinsic nephron progenitor defect, and therefore abnormal nephron number and pattern during kidney development.
Aim 1. Define the role of miR-17~92 gene dosage in establishing nephron number and pattern.
Aim 2. Characterize the intrinsic defect in miR-17~92 null nephron progenitors.
Aim 3. Validate downstream miR-17~92 targets to elucidate mechanism(s) by which the miR-17~92 cluster regulates nephron number and patterning.
Together, these studies seek to define how the miR-17~92 cluster regulates nephron number and patterning during kidney development. To our knowledge, this represents the first known mutation in a miRNA cluster associated with a renal developmental defect. This raises the possibility that regulation of gene expression via miRNAs may be a more general mechanism in the determination of congenital nephron endowment, an important risk factor for chronic kidney disease and hypertension.
|Espiritu, Eugenel B; Crunk, Amanda E; Bais, Abha et al. (2018) The Lhx1-Ldb1 complex interacts with Furry to regulate microRNA expression during pronephric kidney development. Sci Rep 8:16029|
|Phua, Yu Leng; Ho, Jacqueline (2018) Insights into the Regulation of Collecting Duct Homeostasis by Small Noncoding RNAs. J Am Soc Nephrol 29:349-350|
|Phua, Yu Leng; Clugston, Andrew; Chen, Kevin Hong et al. (2018) Small non-coding RNA expression in mouse nephrogenic mesenchymal progenitors. Sci Data 5:180218|
|Liu, Xiaoning; Edinger, Robert S; Klemens, Christine A et al. (2017) A MicroRNA Cluster miR-23-24-27 Is Upregulated by Aldosterone in the Distal Kidney Nephron Where it Alters Sodium Transport. J Cell Physiol 232:1306-1317|
|Cerqueira, Débora M; Bodnar, Andrew J; Phua, Yu Leng et al. (2017) Bim gene dosage is critical in modulating nephron progenitor survival in the absence of microRNAs during kidney development. FASEB J 31:3540-3554|
|Mukherjee, Elina; Maringer, Katherine; Papke, Emily et al. (2017) Endothelial marker-expressing stromal cells are critical for kidney formation. Am J Physiol Renal Physiol 313:F611-F620|
|Phua, Yu L; Ho, Jacqueline (2016) Renal dysplasia in the neonate. Curr Opin Pediatr 28:209-15|
|Hemker, Shelby L; Sims-Lucas, Sunder; Ho, Jacqueline (2016) Role of hypoxia during nephrogenesis. Pediatr Nephrol 31:1571-7|
|Pastor-Soler, Núria M; Sutton, Timothy A; Mang, Henry E et al. (2015) Muc1 is protective during kidney ischemia-reperfusion injury. Am J Physiol Renal Physiol 308:F1452-62|