Autosomal dominant polycystic kidney disease (ADPKD) is an inherited genetic disorder that is caused by mutations in PKD1 or PKD2 genes and is characterized by renal fluid-filled cyst formation and interstitial fibrosis. PKD1 gene mutation results in the upregulation of SET (suppressor of variegation, enhancer of zeste, trithorax) and MYND (myeloid-nervy-DEAF1) domaincontaining lysine methyltransferase 2 (SMYD2) in kidneys from Pkd1 mutant mice and patients with ADPKD. However, the role and mechanism of Smyd2 in the regulation of renal fibrosis in ADPKD remains elusive. In the present study, we showed that 1) expression of Smyd2 can be regulated by transforming growth factor (TGF)-b-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-b-induced expression of a-smooth muscle actin, fibronectin, collagen type 1 and 3, and plasminogen activator inhibitor-1 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 identified a cross talk between TGF-b signaling and Smyd2 in the regulation of fibrotic gene transcription and activation of fibroblasts in cystic kidneys, suggesting that targeting Smyd2 with AZ505 is a potential therapeutic strategy for ADPKD treatment.
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