Lysine methyltransferase SMYD2 promotes cyst growth in autosomal dominant polycystic kidney disease
Linda Xiaoyan Li, … , Julien Sage, Xiaogang Li
Linda Xiaoyan Li, … , Julien Sage, Xiaogang Li
Published June 12, 2017
Citation Information: J Clin Invest. 2017;127(7):2751-2764. https://doi.org/10.1172/JCI90921.
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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 1

Pkd1 mutant renal epithelial cells and tissues demonstrated increased expression of SMYD2.

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Pkd1 mutant renal epithelial cells and tissues demonstrated increased e...
(A) Western blot analysis of SMYD2 expression from whole cell lysates in Pkd1 WT, Pkd1null/null MEK cells (Null), Pkd1-heterozygous PH2 cells, and Pkd1-homozygous PN24 cells (top panel). Relative SMYD2 expression was quantified from 3 independent immunoblots and standardized to actin (bottom panel). (B) qRT-PCR analysis of relative Smyd2 mRNA expression in WT, Null, PH2, and PN24 cells. (C) Western blot analysis of SMYD2 expression in P7 kidneys from Pkd1+/+:Ksp-Cre (WT) and Pkd1fl/fl:Ksp-Cre (Homo) neonates (top panel). Relative SMYD2 expression in the kidneys (bottom panel) as standardized to actin. (D) qRT-PCR analysis of relative Smyd2 mRNA expression in the kidneys described in C. n = 3. (E) Western blot analysis of SMYD2 expression in primary human ADPKD and NHK cells. Data are representative of 2 independent experiments. (F) Immunohistochemistry analysis indicated that SMYD2 expression was increased in cyst-lining epithelia in human ADPKD kidneys (bottom panel) but not in normal human kidneys (top panel). Scale bars: 50 μm. (G) Western blot analysis of SMYD2 expression in mIMCD3 cells with or without knockdown of Pkd1 with shRNA and/or Smyd2 with siRNA. Representative data from 3 independent experiments are shown.