Transcriptome-wide association analysis identifies DACH1 as a kidney disease risk gene that contributes to fibrosis

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

“…Furthermore, the potential effects of increased tubular cell proliferation on kidney structure and function remain unclear. A previous in vitro study reported that high glucose induces proliferation, apoptosis, and an inflammatory response in tubular cells with reduced DACH1 expression (15), which is consistent with the findings by Doke et al (13). The authors also found that miR-218, which is elevated in DKD, negatively regulates DACH1 (15).…”

“…To determine a potential causative role of tubular DACH1 in kidney injury, Doke et al generated two mouse models, one with tubule-specific Dach1 deletion and another with inducible overexpression (13). Similarly to what was found in the study by Cao et al, which analyzed podocyte-specific Dach1 deletion and overexpression (5), mice with tubular Dach1 deletion or overexpression did not develop a phenotype per se (13).…”

“…In this issue of the JCI, Doke et al also identified DACH1 as a candidate gene for kidney disease using a powerful approach that included transcriptome-wide association studies (TWAS), single-cell epigenome analysis, and GWAS in combination with expression analysis, gene editing, and functional validation (13). Using CRISPR-Cas9 gene-editing technology in distal tubular cells, the researchers validated and defined the causal role of an estimated glomerular filtration rate (eGFR) GWAS SNP in regulating DACH1 expression in tubular cells.…”

“…screen of patients with CKD while experimental studies were performed in folic acid-injected mice, a model of AKI and kidney fibrosis (13). Thus, further studies in mouse models of CKD are needed to investigate the role of tubular DACH1 during chronic disease progression.…”

“…Since miR-218 inhibits glucose uptake in cancer (16), it would be interesting to investigate the direct or indirect effects of DACH1 on glucose uptake in renal cells, for example, by regulating SGLT2. Doke et al identified DACH1 as a potential candidate gene in a genetic a positive correlation of DACH1 expression with kidney function and a negative correlation with kidney fibrosis, inflammation, and cell proliferation (13).…”