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Abstract: TH-PO987

Transcription Factor Dach1 in Podocytes

Session Information

Category: Pathology and Lab Medicine

  • 1501 Pathology and Lab Medicine: Basic

Authors

  • Okabe, Masahiro, Tokai University School of Medicine, Isehara, Japan
  • Miyazaki, Yoichi, Jikei University School of Medicine, Tokyo, TOKYO, Japan
  • Yokoo, Takashi, Jikei University School of Medicine, Tokyo, TOKYO, Japan
  • Matsusaka, Taiji, Tokai University School of Medicine, Isehara, Japan
Background

Podocyte injury is crucial for the progression of chronic kidney diseases (CKD). Transcriptional factors, Wt1, Mafb, and Foxc2, are highly expressed in normal podocytes and rapidly decreased upon injury. These play important roles in maintaining normal podocyte function. We aim to find transcriptional factors with similar expression patterns, and study the function in podocytes.

Methods

We combined NEP25 mice, an immunotoxin-inducible podocyte injury model, with RiboTag mice, in which podocyte-specific polysome mRNAs can be yielded by immunoprecipitation in glomerular homogenate. We analyzed gene expression changes of normal and injured podocytes by microarray.

Results

We found the following 8 transcription factor mRNAs were highly expressed in normal podocytes and rapidly decreased after injury; Wt1, Mafb, Foxc2, Tcf21, Foxd2, Banp, Hoxc6, and Dach1. We focused on Dach1 because SNPs of DACH1 gene were associated with the progression of CKD by genome-wide association studies. RT-PCR analysis confirmed that Dach1 mRNA was concentrated in normal podocytes (7.33±0.68-fold vs glomerulus) and decreased in podocytes injured by immunotoxin (0.371±0.0053-fold vs normal podocytes). Immunostaining showed that Dach1 protein was intensely expressed in the nucleus of normal podocytes and decreased upon injury not only in NEP25 model but also in adriamycin nephropathy and HIV-associated nephropathy models. DACH1 protein was also expressed in human normal podocytes and the expression was decreased in diabetic nephropathy, lupus nephritis, and IgA nephropathy but not in minimal change disease. Kockdown of Dach1 by siRNA in murine primary cultured podocytes suppressed the proliferation and DNA synthesis of podocytes, contrasting to the growth inhibitory effect of DACH1 previously reported in cancer cells. The DNA binding sites of DACH1 are reported to co-localize with those of FOX family members. Suppression of Dach1 gene by siRNA in murine primary cultured podocytes decreased the expression of Foxc2-target genes, Podxl and Dpp4 (0.624±0.12 and 0.626±0.29-fold, respectively), suggesting that Dach1 may modulate or collaborate with Foxc2 in podocytes.

Conclusion

Dach1 is highly expressed in normal podocytes and downregulated upon injury. This transcription factor may play a role in maintaining normal podocyte function.

Funding

  • Government Support - Non-U.S.