Activation of podocyte Notch mediates early Wt1 glomerulopathy

Kidney Int. 2018 Apr;93(4):903-920. doi: 10.1016/j.kint.2017.11.014. Epub 2018 Feb 2.


The Wilms' tumor suppressor gene, WT1, encodes a zinc finger protein that regulates podocyte development and is highly expressed in mature podocytes. Mutations in the WT1 gene are associated with the development of renal failure due to the formation of scar tissue within glomeruli, the mechanisms of which are poorly understood. Here, we used a tamoxifen-based CRE-LoxP system to induce deletion of Wt1 in adult mice to investigate the mechanisms underlying evolution of glomerulosclerosis. Podocyte apoptosis was evident as early as the fourth day post-induction and increased during disease progression, supporting a role for Wt1 in mature podocyte survival. Podocyte Notch activation was evident at disease onset with upregulation of Notch1 and its transcriptional targets, including Nrarp. There was repression of podocyte FoxC2 and upregulation of Hey2 supporting a role for a Wt1/FoxC2/Notch transcriptional network in mature podocyte injury. The expression of cleaved Notch1 and HES1 proteins in podocytes of mutant mice was confirmed in early disease. Furthermore, induction of podocyte HES1 expression was associated with upregulation of genes implicated in epithelial mesenchymal transition, thereby suggesting that HES1 mediates podocyte EMT. Lastly, early pharmacological inhibition of Notch signaling ameliorated glomerular scarring and albuminuria. Thus, loss of Wt1 in mature podocytes modulates podocyte Notch activation, which could mediate early events in WT1-related glomerulosclerosis.

Keywords: albuminuria; focal segmental glomerulosclerosis; nephrotic syndrome; podocyte.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Albuminuria / genetics
  • Albuminuria / metabolism
  • Animals
  • Apoptosis
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / metabolism
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Cells, Cultured
  • Disease Models, Animal
  • Epithelial-Mesenchymal Transition
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / metabolism
  • Gene Expression Regulation
  • Glomerulonephritis / genetics
  • Glomerulonephritis / metabolism*
  • Glomerulonephritis / pathology
  • Intracellular Signaling Peptides and Proteins
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Podocytes / metabolism*
  • Podocytes / pathology
  • Proteins / genetics
  • Proteins / metabolism
  • Receptor, Notch1 / genetics
  • Receptor, Notch1 / metabolism*
  • Repressor Proteins / deficiency
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*
  • Signal Transduction
  • Transcription, Genetic
  • WT1 Proteins


  • Apoptosis Regulatory Proteins
  • Basic Helix-Loop-Helix Transcription Factors
  • Forkhead Transcription Factors
  • Hey2 protein, mouse
  • Intracellular Signaling Peptides and Proteins
  • Notch1 protein, mouse
  • Nrarp protein, mouse
  • Proteins
  • Receptor, Notch1
  • Repressor Proteins
  • WT1 Proteins
  • WT1 protein, mouse
  • mesenchyme fork head 1 protein