Early B Cell Factor 1 (EBF1) Regulates Glomerular Development by Controlling Mesangial Maturation and Consequently COX-2 Expression

Le résumé fourni par la source

Significance Statement The specific mechanisms regulating formation of the glomerular tuft during renal development are largely unknown. A previous study showed the transcription factor Early B cell factor 1 (EBF1) is essential for formation of the glomerular tuft. However, the cell types driving glomerular developmental defects in mice lacking EBF1 were not identified. The authors show that deletion of EBF1 from the glomerular mesangium results in impaired glomerular development, whereas deletion of EBF1 from podocytes does not cause developmental abnormalities. They show that EBF1 in the mesangial cells directs glomerular capillary branching through NFAT activation, and consequently COX-2 expression. This is the first evidence that COX-2 inhibition specifically from the mesangial cells impairs renal development, and furthers our understanding of this essential stage of nephrogenesis. Background We recently showed the transcription factor Early B cell factor 1 (EBF1) is essential for the last stages of metanephric development, and that mice globally deficient in EBF1 display impaired maturation of peripheral glomeruli. EBF1 is present within multiple glomerular cell types, including the glomerular mesangium and podocytes. Methods To identify which cell type is driving the glomerular developmental defects in the global EBF1 knockout mice, we deleted EBF1 from the mesangium/pericytes (Foxd1-cre) or podocytes (Podocin-cre) in mice. Results Deletion of EBF1 from Foxd1 lineage cells resulted in hypoplastic kidneys, poorly differentiated peripheral glomeruli, and decreased proximal tubular mass in the outer cortex. Renal insufficiency was apparent at P21 when proteinuria presents, fibrosis of both the glomeruli and interstitium rapidly progresses, microthrombi appear, and hematuria develops. Approximately half of the Foxd1 + , Ebf1 fl/fl mice die before they are 3 months old. Mice with podocyte-targeted deletion of EBF1 exhibited no developmental abnormalities. Mice with Ebf1 deficiency in Foxd1 lineage cells shared characteristics with Ptgs2 /COX-2–insufficient models, and mechanistic investigation revealed impaired calcineurin/NFATc1 activation and decreased COX-2 expression. Deletion of COX-2 from the interstitial/mesangial lineage displayed a less severe phenotype than EBF1 deficiency in mice. Overexpressing COX-2 in the EBF1-deficient mice, however, partially restored glomerular development. Conclusions The results suggest that EBF1 regulates metanephric development at the last stages of glomerular maturation through its actions in the stromal progenitor (Foxd1 + ) lineage where it mediates proper regulation of calcineurin/NFAT signaling and COX-2 expression.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.