Lysine methyltransferase SMYD2 promotes cyst growth in autosomal dominant polycystic kidney disease
Linda Xiaoyan Li, Lucy X. Fan, Julie Xia Zhou, Jared J. Grantham, James P. Calvet, Julien Sage, Xiaogang Li
Linda Xiaoyan Li, Lucy X. Fan, Julie Xia Zhou, Jared J. Grantham, James P. Calvet, Julien Sage, Xiaogang Li
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Research Article Genetics Nephrology

Lysine methyltransferase SMYD2 promotes cyst growth in autosomal dominant polycystic kidney disease

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is driven by mutations in PKD1 and PKD2 genes. Recent work suggests that epigenetic modulation of gene expression and protein function may play a role in ADPKD pathogenesis. In this study, we identified SMYD2, a SET and MYND domain protein with lysine methyltransferase activity, as a regulator of renal cyst growth. SMYD2 was upregulated in renal epithelial cells and tissues from Pkd1-knockout mice as well as in ADPKD patients. SMYD2 deficiency delayed renal cyst growth in postnatal kidneys from Pkd1 mutant mice. Pkd1 and Smyd2 double-knockout mice lived longer than Pkd1-knockout mice. Targeting SMYD2 with its specific inhibitor, AZ505, delayed cyst growth in both early- and later-stage Pkd1 conditional knockout mouse models. SMYD2 carried out its function via methylation and activation of STAT3 and the p65 subunit of NF-κB, leading to increased cystic renal epithelial cell proliferation and survival. We further identified two positive feedback loops that integrate epigenetic regulation and renal inflammation in cyst development: SMYD2/IL-6/STAT3/SMYD2 and SMYD2/TNF-α/NF-κB/SMYD2. These pathways provide mechanisms by which SMYD2 might be induced by cyst fluid IL-6 and TNF-α in ADPKD kidneys. The SMYD2 transcriptional target gene Ptpn13 also linked SMYD2 to other PKD-associated signaling pathways, including ERK, mTOR, and Akt signaling, via PTPN13-mediated phosphorylation.

Authors

Linda Xiaoyan Li, Lucy X. Fan, Julie Xia Zhou, Jared J. Grantham, James P. Calvet, Julien Sage, Xiaogang Li

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Figure 7

PKD-associated signaling pathways could be affected by SMYD2 in Pkd1 mutant renal epithelial cells and cystic tissues.

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PKD-associated signaling pathways could be affected by SMYD2 in Pkd1 mut...
(A and B) Western blot analysis of the phosphorylation of ERK, S6, AKT, and Rb as well as the total protein levels of these proteins in Pkd1-null MEK cells with or without knockdown of Smyd2 with siRNA for 24 hours (A) and with or without AZ505 treatment for 2 hours (B). Representative data are shown from 3 independent experiments. (C) Western blot analysis of the phosphorylation of ERK, S6, AKT, and Rb in kidneys from Pkd1 conditional knockout mice. Data are representative of 2 independent experiments. (D) Western blot analysis of the phosphorylation of ERK, S6, AKT, and Rb, as well as the expression of SMYD2 and PTPN13 in mIMCD3 cells transfected with or without Smyd2 siRNA and/or Ptpn13 siRNA. Representative data from 3 independent experiments are shown.