Foxc1 and Foxc2 are necessary to maintain glomerular podocytes

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Abstract

Foxc1 and Foxc2 (Foxc1/2) are transcription factors involved in many biological processes. In adult kidneys, expression of Foxc1/2 is confined to the glomerular epithelial cells, i.e., podocytes.

To bypass embryonic lethality of Foxc1/2 null mice, mice ubiquitously expressing inducible-Cre (ROSA26-CreERT2) or mice expressing Cre in podocytes (Nephrin-Cre) were mated with floxed-Foxc1 and floxed-Foxc2 mice. The CreERT2 was activated in adult mice by administrations of tamoxifen.

Eight weeks after tamoxifen treatment, ROSA26-CreERT2; Foxc1+/flox; Foxc2flox/flox mice developed microalbuminuria, while ROSA26-Cre ERT2; Foxc1flox/flox; Foxc2+/flox mice had no microalbuminuria. The kidneys of conditional-Foxc1/2 null mice showed proteinaceous casts, protein reabsorption droplets in tubules and huge vacuoles in podocytes, indicating severe podocyte injury and massive proteinuria. Comparison of gene expression profiles revealed that Foxc1/2 maintain expression of genes necessary for podocyte function such as podocin and Cxcl12. In addition, mice with an innate podocyte-specific deletion of Foxc1/2 by Nephrin-Cre develop similar podocyte injury.

These results demonstrate dose-dependence of Foxc1/2 gene in maintaining the podocyte with a more critical role for Foxc2 than Foxc1 and a critical role of Foxc1/2 in regulating expression of genes that maintain podocyte integrity.

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