DACH1 protects podocytes from experimental diabetic injury and modulates PTIP-H3K4Me3 activity

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

“…Cao and colleagues identified DACH1 as a major regulator of podocyte structure and function (5). Analyzing available glomerular transcriptomic data sets, they found reduced DACH1 mRNA levels in different human glomerular diseases, including several forms of nephrotic syndrome and particularly in patients with DKD, an observation that is consistent with a previous report demonstrating endothelium, build the glomerular filtration barrier.…”

“…It is interesting that two independent studies identify DACH1 as a susceptibility factor for kidney diseases, including DKD and nephrotic syndrome, although each group focused on a different cell type, i.e., podocytes or tubular cells (5,13). The finding that diminished DACH1 expression in either cell type is insufficient to cause injury, but renders the cells susceptible to injury, supports the hypothesis of a multihit injury process in the pathogenesis of kidney diseases.…”

“…Mice with a homozygous Dach1 deletion die early, although no morphological or metabolic alterations in any organs were detected (4). In this issue of the JCI, Cao et al report the development of Dach1-deficient mice, which were born at expected Mendelian ratios, but died two days after birth, presenting with renal hypoplasia and dramatic glomerular anomalies, including podocyte maturation failure in the absence of gross abnormalities in other major organs (5).…”

“…These studies suggest an important role for podocyte DACH1 as a susceptibility factor in hyperglycemiainduced kidney injury (Figure 1). To investigate a podocyte-specific role of DACH1 in nephrotic syndrome, the authors injected Dach1-deficient mice with adriamycin, a recognized agent that induces podocyte injury, and found that Dach1 deficiency rendered mice susceptible to adriamycininduced nephropathy (5).…”

Recent Advances in Diabetic Kidney Diseases: From Kidney Injury to Kidney Fibrosis

“…Dachshund homolog 1 (DACH1) is another transcription factor that is related to DKD. DACH1 recruits Pax transactivation-domain interacting protein (PTIP) to repress transcription in podocytes; this requires DACH1 sequence-specific DNA binding and reduces methylation of histone H3 at K4 to activate the transcription of NELL2 and increase podocyte injury [ 107 ].…”