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.
MeSH terms
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Animals
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Benzoxazines / pharmacology
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Cell Proliferation*
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Cysts / drug therapy
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Cysts / enzymology*
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Cysts / genetics
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Cysts / pathology
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Epigenesis, Genetic*
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Epithelial Cells / enzymology*
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Epithelial Cells / pathology
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Histone-Lysine N-Methyltransferase / antagonists & inhibitors
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Histone-Lysine N-Methyltransferase / genetics
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Histone-Lysine N-Methyltransferase / metabolism*
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MAP Kinase Signaling System*
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Methylation / drug effects
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Mice
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Mice, Mutant Strains
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Polycystic Kidney, Autosomal Dominant
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Protein Kinase C / genetics
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Protein Kinase C / metabolism
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Protein Tyrosine Phosphatase, Non-Receptor Type 13 / genetics
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Protein Tyrosine Phosphatase, Non-Receptor Type 13 / metabolism
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Proto-Oncogene Proteins c-akt / genetics
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Proto-Oncogene Proteins c-akt / metabolism
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STAT3 Transcription Factor / genetics
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STAT3 Transcription Factor / metabolism
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TOR Serine-Threonine Kinases / genetics
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TOR Serine-Threonine Kinases / metabolism
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TRPP Cation Channels / genetics
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TRPP Cation Channels / metabolism
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Transcription Factor RelA / genetics
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Transcription Factor RelA / metabolism
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beta-Alanine / analogs & derivatives
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beta-Alanine / pharmacology
Substances
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AZ 505
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Benzoxazines
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Rela protein, mouse
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STAT3 Transcription Factor
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Stat3 protein, mouse
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TRPP Cation Channels
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Transcription Factor RelA
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polycystic kidney disease 2 protein
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beta-Alanine
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Histone-Lysine N-Methyltransferase
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Smyd2 protein, mouse
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mTOR protein, mouse
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protein kinase D
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Proto-Oncogene Proteins c-akt
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TOR Serine-Threonine Kinases
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Protein Kinase C
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Protein Tyrosine Phosphatase, Non-Receptor Type 13
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Ptpn13 protein, mouse