# Dach1 is essential for maintaining normal mature podocytes

## TL;DR

This study shows that Dach1 is crucial for maintaining the health of mature podocytes, which are important for kidney function.

## Contribution

The study demonstrates that Dach1 is essential for maintaining mature podocytes, not for their initial formation.

## Key findings

- Global Dach1 knockout mice had normal kidney structure and podocyte phenotypes at birth.
- Podocyte-specific Dach1 knockout led to albuminuria and glomerulosclerosis in most mice.
- Dach1 is necessary for maintaining mature podocyte integrity but not for their differentiation.

## Abstract

Dach1 is highly expressed in normal podocytes, but this expression rapidly disappears after podocyte injury. To investigate the role of Dach1 in podocytes in vivo, we analyzed global, podocyte-specific, and inducible Dach1 knockout mice. Global Dach1 knockout (Dach1-/-) mice were assessed immediately after birth because they die within a day. The kidneys of Dach1-/- mice were slightly smaller than those of control mice but maintained a normal structure and normal podocyte phenotypes, including ultrastructure. To study the role of Dach1 in mature podocytes, we generated Dach1 knockout mice by mating Dach1fl/fl mice with Nphs1-Cre or ROSA-CreERT2 mice. Due to inefficient Cre recombination, only a small number of podocytes lacked Dach1 staining in these mice. However, all eleven Nphs1-Cre/Dach1fl/fl mice displayed abnormal albuminuria, and seven (63%) of them developed focal segmental glomerulosclerosis. Among 13 ROSA-CreERT2/Dach1fl/fl mice, eight (61%) exhibited abnormal albuminuria after treatment with tamoxifen, and five (38%) developed early sclerotic lesions. These results indicate that while Dach1 does not determine the fate of differentiation into podocytes, it is indispensable for maintaining the normal integrity of mature podocytes.