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

Research output: Contribution to journalArticle

12 Citations (Scopus)

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 doubleknockout 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.

Original languageEnglish (US)
Pages (from-to)2751-2764
Number of pages14
JournalJournal of Clinical Investigation
Volume127
Issue number7
DOIs
StatePublished - Jun 30 2017
Externally publishedYes

Fingerprint

Autosomal Dominant Polycystic Kidney
Methyltransferases
Lysine
Cysts
Kidney
Growth
Knockout Mice
Epigenomics
Interleukin-6
Histone-Lysine N-Methyltransferase
Epithelial Cells
Cyst Fluid
MAP Kinase Signaling System
Methylation
Genes
Cell Survival
Epithelium
Phosphorylation
Cell Proliferation
Inflammation

ASJC Scopus subject areas

  • Medicine(all)

Cite this

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

In: Journal of Clinical Investigation, Vol. 127, No. 7, 30.06.2017, p. 2751-2764.

Research output: Contribution to journalArticle

Li, Linda Xiaoyan ; Fan, Lucy X. ; Zhou, Julie Xia ; Grantham, Jared J. ; Calvet, James P. ; Sage, Julien ; Li, Xiaogang. / Lysine methyltransferase SMYD2 promotes cyst growth in autosomal dominant polycystic kidney disease. In: Journal of Clinical Investigation. 2017 ; Vol. 127, No. 7. pp. 2751-2764.
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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 doubleknockout 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.",
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