Twisted gastrulation, a BMP antagonist, exacerbates podocyte injury

PLoS One. 2014 Feb 25;9(2):e89135. doi: 10.1371/journal.pone.0089135. eCollection 2014.

Abstract

Podocyte injury is the first step in the progression of glomerulosclerosis. Previous studies have demonstrated the beneficial effect of bone morphogenetic protein 7 (Bmp7) in podocyte injury and the existence of native Bmp signaling in podocytes. Local activity of Bmp7 is controlled by cell-type specific Bmp antagonists, which inhibit the binding of Bmp7 to its receptors. Here we show that the product of Twisted gastrulation (Twsg1), a Bmp antagonist, is the central negative regulator of Bmp function in podocytes and that Twsg1 null mice are resistant to podocyte injury. Twsg1 was the most abundant Bmp antagonist in murine cultured podocytes. The administration of Bmp induced podocyte differentiation through Smad signaling, whereas the simultaneous administration of Twsg1 antagonized the effect. The administration of Bmp also inhibited podocyte proliferation, whereas simultaneous administration of Twsg1 antagonized the effect. Twsg1 was expressed in the glomerular parietal cells (PECs) and distal nephron of the healthy kidney, and additionally in damaged glomerular cells in a murine model of podocyte injury. Twsg1 null mice exhibited milder hypoalbuminemia and hyperlipidemia, and milder histological changes while maintaining the expression of podocyte markers during podocyte injury model. Taken together, our results show that Twsg1 plays a critical role in the modulation of protective action of Bmp7 on podocytes, and that inhibition of Twsg1 is a promising means of development of novel treatment for podocyte injury.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Morphogenetic Protein 7 / antagonists & inhibitors*
  • Bone Morphogenetic Protein 7 / metabolism*
  • Cell Differentiation / physiology
  • Cells, Cultured
  • Kidney Glomerulus / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nephrons / metabolism
  • Podocytes / metabolism*
  • Proteins / metabolism*
  • Signal Transduction / physiology
  • Smad Proteins / metabolism

Substances

  • Bone Morphogenetic Protein 7
  • Proteins
  • Smad Proteins
  • bmp7 protein, mouse
  • twisted gastrulation protein, mouse

Grant support

This study was supported by the Japan Society of the Promotion of Science (JSPS) through the Funding Program for Next-Generation World-Leading Researchers (NEXT program), Grants-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan (Shin-gakujyutsu 21200080), and grants from the Astellas Foundation for Research on Metabolic Disorders. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.