Transcription factor 21 deletion from podocyte precursors as a model for congenital nephrotic syndrome.

Nephrotic syndrome is one of the most common causes of kidney disease in children. The glomerular and tubulointerstitial changes that occur in the kidney due to this state of high-grade proteinuria are incompletely understood. Here, we report a mouse model of congenital nephrotic syndrome, induced by deletion of transcription factor 21 (Tcf21) from podocyte precursors, that can be used to study the injury sustained by young kidneys in response to nephrotic range proteinuria. Tcf21 is required for normal podocyte development. Our laboratory previously showed that deletion of Tcf21 from early podocyte progenitors abrogated the formation of normal foot processes in embryonic mice. We now show the postnatal phenotype of this deletion characterized by progressive nephrotic range proteinuria as early as two weeks of age. These mice developed worsening glomerulosclerosis and tubulointerstitial fibrosis, resulting in early mortality. Single-cell RNA sequencing of kidneys from these mice demonstrated structural and developmental defects in podocytes caused by the absence of Tcf21. Parietal epithelial cells in mutant kidneys underwent secondary changes that have been shown to promote glomerular injury in other models of kidney disease. In addition, we observed tubulointerstitial changes coincident with the massive proteinuria produced by this genetic model-namely, an expansion of fibroblasts accompanied by the appearance of a new injury cell state in the loop of Henle. These changes preceded the onset of severe, irreversible injury, presenting pathways that could be intervened upon early in the disease to prevent progression of renal fibrosis.NEW & NOTEWORTHY This study generated a comprehensive kidney-wide single-cell transcriptomic dataset of a murine model of childhood nephrotic syndrome developed by the deletion of transcription factor 21 (Tcf21) from early podocyte precursors. Our transcriptomic data provide further mechanistic insights into how TCF21 regulates podocyte health and development while enabling interrogation of how the tubulointerstitium responds to massive proteinuria.