Loss of the podocyte-expressed transcription factor Tcf21/Pod1 results in
podocyte differentiation defects and FSGS
#MMPMID24904088
Maezawa Y
; Onay T
; Scott RP
; Keir LS
; Dimke H
; Li C
; Eremina V
; Maezawa Y
; Jeansson M
; Shan J
; Binnie M
; Lewin M
; Ghosh A
; Miner JH
; Vainio SJ
; Quaggin SE
J Am Soc Nephrol
2014[Nov]; 25
(11
): 2459-70
PMID24904088
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Podocytes are terminally differentiated cells with an elaborate cytoskeleton and
are critical components of the glomerular barrier. We identified a bHLH
transcription factor, Tcf21, that is highly expressed in developing and mature
podocytes. Because conventional Tcf21 knockout mice die in the perinatal period
with major cardiopulmonary defects, we generated a conditional Tcf21 knockout
mouse to explore the role of this transcription factor in podocytes in vivo.
Tcf21 was deleted from podocytes and podocyte progenitors using podocin-cre
(podTcf21) and wnt4-cre (wnt4creTcf21) driver strains, respectively. Loss of
Tcf21 from capillary-loop stage podocytes (podTcf21) results in simplified
glomeruli with a decreased number of endothelial and mesangial cells. By 5 weeks
of age, 40% of podTcf21 mice develop massive proteinuria and lesions similar to
FSGS. Notably, the remaining 60% of mice do not develop proteinuria even when
aged to 8 months. By contrast, earlier deletion of Tcf21 from podocyte precursors
(wnt4creTcf21) results in a profound developmental arrest of podocyte
differentiation and renal failure in 100% of mice during the perinatal period.
Taken together, our results demonstrate a critical role for Tcf21 in the
differentiation and maintenance of podocytes. Identification of direct targets of
this transcription factor may provide new therapeutic avenues for proteinuric
renal disease, including FSGS.
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