Crosstalk between lysine methyltransferase Smyd2 and TGF-β-Smad3 signaling promotes renal fibrosis in autosomal dominant polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) is an inherited genetic disorder, which is caused by mutations of PKD1 or PKD2 gene and is characterized by renal fluid-filled cyst formation and interstitial fibrosis. PKD1 gene mutation results in the upregulation of SET and MYND domain-containing lysine methyltransferase 2 (SMYD2) in Pkd1 mutant mouse and ADPKD patient kidneys. However, the role and mechanism of Smyd2 in the regulation of renal fibrosis in ADPKD remains elusive. In this study, we show that: 1) the expression of Smyd2 can be regulated by TGF-β-Smad3 in normal rat kidney 49F (NRK-49F) cells and mouse fibroblast NIH3T3 cells; 2) knockdown of Smyd2 and inhibition of Smyd2 with its specific inhibitor, AZ505, decreases TGF-β-induced expression of α-smooth muscle actin (α-SMA), fibronectin, collagens 1 and 3 and plasminogen activator inhibitor-1( PAI1) in NRK-49F cells; 3) Smyd2 regulates the transcription of fibrotic marker genes through binding on the promoters of those genes or through methylating histone H3 to indirectly regulate the expression of those genes; and 4) knockout and inhibition of Smyd2 significantly decreases renal fibrosis in Pkd1 knockout mice, supporting that targeting Smyd2 can not only delay cyst growth but also attenuate renal fibrosis in ADPKD. This study identifies a crosstalk between TGF-β signaling and Smyd2 in the regulation of fibrotic gene transcription and the activation of fibroblasts in cystic kidneys, suggesting that targeting Smyd2 with AZ505 is a potential therapeutic strategy for ADPKD treatment.