The absence of Trim28 in nephron progenitors results in impaired kidney development and function

ABSTRACT The TRIM28 gene encodes a transcriptional regulator involved in a variety of molecular processes. Inactivation of TRIM28 has been linked to the epithelial subtype of Wilms tumor, the most common pediatric renal malignancy. Therefore, TRIM28 may impact early kidney morphogenesis. To investigate its role in nephrogenesis, we analyzed Trim28 conditional knockout (Trim28Δ/Δ) mice. We found that deleting Trim28 in nephron progenitors resulted in early postnatal lethality and reduced kidney weight. While all renal structures were present, the proximal tubules (PTs) were disorganized. Transcriptome analyses revealed cell type-specific deregulation of retroelement expression following Trim28 deletion. Further analysis of scRNA-seq data revealed a decreased frequency of nephron progenitor cells (NPCs), an increase in PT cells and a clear shift towards inflammatory gene expression patterns. While there was no evidence of tumor formation in Trim28Δ/Δ kidneys, the differentially expressed genes in Trim28Δ/Δ progenitors reflected reduced translation, similar to patterns observed in TRIM28 mutant tumor-derived NPCs. Thus, our data demonstrate that TRIM28 primarily influences the maintenance and differentiation of NPCs and PT cells, as well as their subsequent function.