Loss of the podocyte-expressed transcription factor Tcf21/Pod1 Results in podocyte differentiation defects and FSGS

Yoshiro Maezawa, Tuncer Onay, Rizaldy P. Scott, Lindsay S. Keir, Henrik Dimke, Chengjin Li, Vera Eremina, Yuko Maezawa, Marie Jeansson, Jingdong Shan, Matthew Binnie, Moshe Lewin, Asish Ghosh, Jeffrey H. Miner, Seppo J. Vainio, Susan E. Quaggin*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2459-2470
Number of pages12
JournalJournal of the American Society of Nephrology
Volume25
Issue number11
DOIs
StatePublished - Nov 1 2014

ASJC Scopus subject areas

  • Nephrology

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