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Kidney Week

Abstract: PO1969

Dach1 Is Essential for Maintaining Normal Podocytes

Session Information

  • Podocyte Biology
    October 22, 2020 | Location: On-Demand
    Abstract Time: 10:00 AM - 12:00 PM

Category: Glomerular Diseases

  • 1204 Podocyte Biology

Authors

  • Tanaka, Keiko, Department of Basic Medicine, Tokai University School of Medicine, Isehara, Japan
  • Matsusaka, Taiji, Department of Basic Medicine, Tokai University School of Medicine, Isehara, Japan
Background

Dach1 is a transcription factor, determining cell fates in various organs. Dach1 polymorphism has been reported to be associated with nephrotic syndrome and chronic kidney diseases. We previously found that Dach1 was highly expressed in normal podocytes and rapidly disappeared after induction of podocyte injury, similarly to WT1. We, therefore, aimed to elucidate the function of Dach1 in normal podocytes in vivo.

Methods

Podocyte-specific Dach1-knockout (KO) mice were generated by mating Dach1-flox mice with Nphs1-Cre or Nphs2-CreERT2 mice. Podocyte injury was evaluated by urinalysis (SDS-PAGE) and histology. In addition, we analyzed primary cultured podocytes of Dach1 overexpressing knock-in transgenic (KI) mice (n=9), in which Dach1 is expressed under the control of Rosa26 promoter.

Results

Although the efficiency of Cre-mediated recombination was not high, all of the congenital Dach1-KO mice (n=20, more than 4 weeks old) presented abnormal albuminuria. Seven out of the 11 (63%) mice histologically analyzed showed focal segmental glomerulosclerosis. Injured podocytes lacked Dach1 staining, whereas intact podocytes retained Dach1. When Dach1 KO was induced in adult mice, the mice showed abnormal albuminuria within two weeks. Immunostaining revealed that podocytes lacking Dach1 causes leakage of albumin, while retaining WT1 protein. Since endogenous Dach1 expression in podocytes is very high compared with transgenic expression of Dach1 driven by the Rosa26 promoter, we analyzed primary cultured podocytes, in which endogenous Dach1 was downregulated. Dach1 mRNA was 3.8-fold higher (p=0.0007) in Dach1-KI podocytes than in control podocytes. We previously found that Dpp4 is one of the candidate target genes of Dach1 by knockdown experiments. Dpp4 mRNA in Dach1-KI podocytes was found to be increased (1.5-fold, p=0.0022).

Conclusion

These results indicate that Dach1 is important in maintaining normal podocyte integrity, and Dach1 gene deficiency induces podocyte injury.