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Abstract: PO1699

Dach1 Is Essential for Maintaining Normal Podocytes

Session Information

Category: Glomerular Diseases

  • 1204 Podocyte Biology

Authors

  • Tanaka, Keiko, Okayama Daigaku Daigakuin Ishiyakugaku Sogo Kenkyuka, Okayama, Okayama, Japan
  • Matsusaka, Taiji, Tokai Daigaku Igakubu Daigakuin Igaku Kenkyuka, Isehara, Kanagawa, 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 aimed to elucidate the function of Dach1 in podocytes in vivo.

Methods

Because Dach1 null mice die shortly after birth, kidneys were harvested at P0 and histologically examined.
To study the role of Dach1 in mature podocytes, podocyte-specific Dach1 deleted mice were generated by mating Dach1fl/fl mice with Nphs1-Cre or Nphs2-CreERT2 mice. Eleven Nphs1-Cre/Dach1fl/fl mice were analyzed at 8-35 weeks of age. 14 Nphs2-CreERT2/Dach1fl/fl mice were treated with tamoxifen (0.1mg/g BW/day, p.o. 5 days 3 courses) and analyzed 7 days later.

Results

In neonatal wild-type mice, Dach1 is faintly expressed in the cap mesenchyme and increased in the renal vesicles/S-shaped bodies and further intensified and concentrated in mature podocytes. Dach1 is also intensely expressed in the ureteric bud.
In Dach1 null mice, negative Dach1 staining was confirmed. Kidneys of Dach1 null mice were 14.2 % smaller than those of control mice but showed normal structure. Podocytes in Dach1 null mice showed normal phenotypes in SEM and TEM with normal slit membrane, and no abnormal leakage of albumin. Immunostaining for WT1, nephrin, podocin, synaptopodin and nestin was normal.
Only a small number of podocytes lacked Dach1 staining in Nphs1-Cre/Dach1fl/fl and Nphs2-CreERT2/Dach1fl/fl mice, indicating inefficient Cre-mediated recombination. Nevertheless, all Nphs1-Cre/Dach1fl/fl exhibited abnormal albuminuria (UACR 4.7±1.6 mg/mg vs 0.06±0.007), which increased with age, and seven (63%) mice showed FSGS. Seven (50%) Nphs2-CreERT2/Dach1fl/fl mice exhibited abnormal albuminuria, and three (21%) mice showed early sclerotic lesions. Immunostaining showed that sclerotic lesions lacked Dach1 as well as WT1, synaptopodin and nephrin. Most of Dach1 negative podocytes in non-sclerotic glomeruli had normal staining for podocyte marker proteins.

Conclusion

These results indicate that Dach1 does not determine the fate of differentiation into podocytes but is indispensable for maintaining normal integrity of mature podocytes.

Funding

  • Government Support – Non-U.S.