The transcription factor Tcf21 is required for specifying Foxd1 cells to the juxtaglomerular cell lineage

Renin is a crucial enzyme involved in the regulation of blood pressure and electrolyte balance. It has been shown that renin expressing cells arise from the Foxd1+ stromal progenitors, however the factors involved in guiding Foxd1+ cells towards the renin-secreting cell fate remain poorly understood. Tcf21, also known as Pod1 or Capsulin, is a bHLH transcription factor that is expressed in the metanephric mesenchyme and plays a crucial role in kidney development. We have previously shown that deletion of Tcf21 in Foxd1+ cells ( Foxd1 ^Cre/+ ;Tcf21 ^f/f ) results in paucity of vascular mural cells and in disorganized renal arterial tree with fewer, shorter, and thinner arterioles. Here, we sought to examine the relationship between Tcf21 and renin cells during kidney development and test whether Tcf21 is implicated in the regulation of juxtaglomerular cell differentiation. Immunostaining for renin demonstrated that kidneys of Foxd1 ^Cre/+ ;Tcf21 ^f/f have fewer renin-positive spots at E16.5 and E18.5 compared with controls. In-situ hybridization for renin mRNA showed reduced expression in Foxd1 ^Cre/+ ;Tcf21 ^f/f kidneys at E14.5, E16.5, and E18.5. Together, these data suggest that stromal expression of Tcf21 is required for the emergence of renin cells. To dissect the role of Tcf21 in juxtaglomerular (JG) cells, we deleted Tcf21 upon renin promoter activation ( Ren1 ^dCre/+ ;Tcf21 ^f/f ). Interestingly, the Ren1 ^dCre/+ ;Tcf21 ^f/f kidney showed normal arterial tree at E16.5 identical to controls. Furthermore, inactivation of Tcf21 upon renin expression did not alter kidney morphology in two- and four-month-old mice. Finally, expression renin mRNA was similar between Ren1 ^dCre/+ ;Tcf21 ^f/f and controls at 2 months.

Taken together, these findings suggest that Tcf21 expression in Foxd1+ cells is essential for specifying the fate of these cells into juxtaglomerular cells. However, once renin cell identity is assumed, Tcf21 is dispensable. Uncovering the regulation of Foxd1+ cells and their derivatives, including the JG cell lineage, is crucial for understanding the mechanisms underlying renal vasculature formation.