Chronic kidney disease (CKD) is a worldwide public health problem that affects millions of men and women of all ages and racial groups. Loss of mesangial cells (MC) represents an early common feature in the pathogenesis of CKD. Transforming growth factor‐β1 (TGF‐β1) is a key inducer of kidney damage and triggers several pathological changes in renal cells, notably MC apoptosis. However, the mechanism of MC apoptosis induced by TGF‐β1 remains elusive. Here, we demonstrate for the first time a novel regulatory pathway in which the disheveled‐binding antagonist of β‐catenin 1 (Dact1) gene is upregulated by TGF‐β1, inducing MC apoptosis. We also show that the inhibitory effect of Dact1 and TGF‐β1 on the transcriptional activation of the pro‐survival Wnt pathway is the mechanism of death induction. In addition, Dact1 mRNA/protein levels are increased in kidney remnants from 5/6 nephrectomized rats and strongly correlate with TGF‐β1 expression. Together, our results point to Dact1 as a novel element controlling MC survival that is causally related to CKD progression. J. Cell. Physiol. 232: 2104–2111, 2017. © 2016 Wiley Periodicals, Inc. Here, we demonstrate for the first time a novel regulatory pathway in which the disheveled‐binding antagonist of β‐catenin 1 (Dact1) gene is upregulated by TGF‐β1, inducing MC apoptosis.