DACH1 as a multifaceted and potentially druggable susceptibility factor for kidney disease

Abstract

Kidney diseases affect more than 15% of adults in the US, yet drug development in the kidney field, when compared with that for other common diseases, has been lagging behind. Modifiers that increase the susceptibility to injury and contribute to the pathogenesis and progression of kidney disease include genetic and environmental factors and epigenetic mechanisms. In this issue of the JCI, Cao et al. and Doke et al. independently report the identification of a susceptibility factor called Dachshund homolog 1 (DACH1). Both groups identify an association of reduced DACH1 expression with kidney disease, using different screening approaches, studying different types of human kidney diseases, and using different experimental models, making the fact that both stumbled over the same protein very compelling. Combined, these studies highlight DACH1 as a key safeguard in the kidney, granting various cell types proper function by modulating several molecular pathways.

Figure 1. Decreased podocyte and tubular DACH1 expression is a susceptibility factor for various kidney diseases.

In podocytes (left), DACH1 is a safeguard in the nucleus that limits histone H3 lysine 4 trimethylation (H3K4Me3), thereby preventing transcriptional activation of several genes. DACH1 interacts with pax transactivation-domain interacting protein (PTIP), an essential component of the H3K4Me3 complex, which results in reduced promoter methylation and transcriptional repression. Modifiers, which can be of genetic, epigenetic, or environmental origin, can lead to reduced DACH1 expression and to transcriptional derepression of target genes, making podocytes more susceptible to a second insult. A second insult, such as high glucose levels, may ultimately cause podocyte injury and albuminuria. In tubular cells (right), DACH1 acts as a transcriptional suppressor of cell-cycle genes and of proinflammatory cytokines. Modifiers leading to reduced tubular DACH1 expression and to transcriptional derepression of target genes make the tubular cells more susceptible to a second insult, such as folic acid–induced kidney injury or hyperglycemia, ultimately causing tubular cell proliferation or injury and eventually renal inflammation and fibrosis. For both cell types, modifiers and mechanisms that induce the reduction of DACH1 expression are currently unknown.