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

J Clin Invest. 2017 Jun 30;127(7):2751-2764. doi: 10.1172/JCI90921. Epub 2017 Jun 12.

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

  • Animals
  • Benzoxazines / pharmacology
  • Cell Proliferation*
  • Cysts / drug therapy
  • Cysts / enzymology*
  • Cysts / genetics
  • Cysts / pathology
  • Epigenesis, Genetic*
  • Epithelial Cells / enzymology*
  • Epithelial Cells / pathology
  • Histone-Lysine N-Methyltransferase / antagonists & inhibitors
  • Histone-Lysine N-Methyltransferase / genetics
  • Histone-Lysine N-Methyltransferase / metabolism*
  • MAP Kinase Signaling System*
  • Methylation / drug effects
  • Mice
  • Mice, Mutant Strains
  • Polycystic Kidney, Autosomal Dominant
  • Protein Kinase C / genetics
  • Protein Kinase C / metabolism
  • Protein Tyrosine Phosphatase, Non-Receptor Type 13 / genetics
  • Protein Tyrosine Phosphatase, Non-Receptor Type 13 / metabolism
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / metabolism
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / metabolism
  • TRPP Cation Channels / genetics
  • TRPP Cation Channels / metabolism
  • Transcription Factor RelA / genetics
  • Transcription Factor RelA / metabolism
  • beta-Alanine / analogs & derivatives
  • beta-Alanine / pharmacology

Substances

  • AZ 505
  • Benzoxazines
  • Rela protein, mouse
  • STAT3 Transcription Factor
  • Stat3 protein, mouse
  • TRPP Cation Channels
  • Transcription Factor RelA
  • polycystic kidney disease 2 protein
  • beta-Alanine
  • Histone-Lysine N-Methyltransferase
  • Smyd2 protein, mouse
  • mTOR protein, mouse
  • protein kinase D
  • Proto-Oncogene Proteins c-akt
  • TOR Serine-Threonine Kinases
  • Protein Kinase C
  • Protein Tyrosine Phosphatase, Non-Receptor Type 13
  • Ptpn13 protein, mouse