Drosha in mesangial cells regulates glomerular capillary tufts formation through drosha/ribosome/Gata3 axis

Abstract Drosha is a critical regulator of kidney development; its loss or mutation, identified in a subsets of Wilms tumor (WT), a pediatric kidney cancer, leads to nephric cap mesenchyme developmental defects. Here, we investigated the role of Drosha in mesangial cells and its impact on glomerular capillary tuft formation. Mesangial cells specific deletion of Drosha (Drosha cKO) in mouse model was generated. Deletion of Drosha in mesangial cells disrupted the glomerular capillary tufts formation, leading to dysplastic glomeruli, proteinuria, oliguria, reduced looping of glomerular capillaries and capillary dilation. Drosha knockdown in mesangial cells (SV40 MES 13) leads to decreased cell proliferation and reduced Gata3 protein level. Transcriptome analysis by RNA-seq shows decreased levels of ribosomal protein genes (RPGs) but unaltered mRNA levels of major genes affecting kidney development, including Gata3, Pax2, Atn1, Wt1 etc. in Drosha-KD compared to Control SV40 MES13 cells. Further analysis indicates Drosha regulates the translation of Gata3 in mesangial cells via regulating RPG transcription. Removal of Drosha in adult mesangial cells did not cause significant kidney dysfunction, indicating that Drosha functions primarily during development rather than in homeostasis. Our work reveals that Drosha in mesangial cells orchestrates the formation of glomerular capillary tufts by regulating Gata3 translation. It identifies the critical role of DROSHA in nephric development and proposes DROSHA as a novel potential causal gene for congenital anomalies of the kidney and the urinary tract (CAKUT).