Bimgene dosage is critical in modulating nephron progenitor survival in the absence of microRNAs during kidney development

Abstract

Low nephron endowment at birth has been associated with an increased risk for developing hypertension and chronic kidney disease. We demonstrated in an earlier study that conditional deletion of the microRNA (miRNA)-processing enzyme Dicer from nephron progenitors results in premature depletion of the progenitors and increased expression of the proapoptotic protein Bim (also known as Bcl-2L11). In this study, we generated a compound mouse model with conditional deletion of both and, to determine the biologic significance of increased Bim expression in -deficient nephron progenitors. The loss of partially restored the number of nephron progenitors and improved nephron formation. The number of progenitors undergoing apoptosis was significantly reduced in kidneys with loss of a single allele, or both alleles, of compared to mutant kidneys. Furthermore, 2 miRNAs expressed in nephron progenitors ( and regulated Bim levels and Together, these data suggest that miRNA-mediated regulation of Bim controls nephron progenitor survival during nephrogenesis, as one potential means of regulating nephron endowment.-Cerqueira, D. M., Bodnar, A. J., Phua, Y. L., Freer, R., Hemker, S. L., Walensky, L. D., Hukriede, N. A., Ho, J. gene dosage is critical in modulating nephron progenitor survival in the absence of microRNAs during kidney development.

Von Hippel-Lindau Acts as a Metabolic Switch Controlling Nephron Progenitor Differentiation

“…Samples were immunostained with anti-Wt1 (1:100; Cell Signaling Technologies), and visualized using a Vectastain ABC Kit (Vector Laboratories). 32 Every 20 sections, Wt1 + structures were identified from consecutive sections using a Zeiss Model Axio Imager M1 (Zeiss) microscope with Stereo Investigator Stereology image tracing software (MBF Bioscience). Glomerular number was quantified using the equation by Cullen-McEwen et al 30 Serum Analysis P21 mice were anesthetized and subject to cardiac puncture for blood collection.…”

“…E13.5 kidneys were cultured on 0.4 mm polyethylene terephthalate membrane inserts as previously described. 32 One kidney from each embryo was cultured in improved minimal essential media (containing 50 mg/ml transferrin) alone and the other was cultured in media containing 10 mM YN1 inhibitor. 22,32 After 72 hours kidneys were fixed in 4% paraformaldehyde for 1 hour.…”

“…32 One kidney from each embryo was cultured in improved minimal essential media (containing 50 mg/ml transferrin) alone and the other was cultured in media containing 10 mM YN1 inhibitor. 22,32 After 72 hours kidneys were fixed in 4% paraformaldehyde for 1 hour. Kidneys were immunostained with antibodies against Six2 and Jag1, following previously described methods.…”

“…Kidneys were immunostained with antibodies against Six2 and Jag1, following previously described methods. 32…”

Deletion of hypoxia‐responsive microRNA‐210 results in a sex‐specific decrease in nephron number

“…miRNAs are small, endogenous non‐coding RNAs (~22 nucleotides long) that primarily fine‐tune gene expression post‐transcriptionally to regulate various biological processes . Recent studies have identified miRNAs as important regulators of kidney development, particularly as inhibitors of nephron progenitor apoptosis . microRNA‐210‐3p ( miR‐210 ) is the most commonly induced hypoxia‐sensitive miRNA .…”