Type

Journal Article

Authors

Finian Martin
Derek P. Brazil
Sergio Mezzano
Clemens D Cohen
Matthias Kretzler
Desmond G Higgins
Celine C Berthier
Paul McGettigan
Sarah A Roxburgh
David W Walsh

Subjects

Biochemistry

Topics
cell line transforming growth factor beta1 bone morphogenetic proteins cktsf1b1 protein rat mice drug effects humans gene expression regulation basic helix loop helix transcription factors receptors notch genetics metabolism serrate proteins signal transduction intercellular signaling peptides and proteins calcium binding proteins cktsf1b1 protein mouse membrane proteins grem1 protein human pharmacology animals rats promoter regions genetic biopsy epithelial cells binding sites diabetic nephropathies gene expression profiling

Co-regulation of Gremlin and Notch signalling in diabetic nephropathy. (2007)

Abstract Diabetic nephropathy is currently the leading cause of end-stage renal disease worldwide, and occurs in approximately one third of all diabetic patients. The molecular pathogenesis of diabetic nephropathy has not been fully characterized and novel mediators and drivers of the disease are still being described. Previous data from our laboratory has identified the developmentally regulated gene Gremlin as a novel target implicated in diabetic nephropathy in vitro and in vivo. We used bioinformatic analysis to examine whether Gremlin gene sequence and structure could be used to identify other genes implicated in diabetic nephropathy. The Notch ligand Jagged1 and its downstream effector, hairy enhancer of split-1 (Hes1), were identified as genes with significant similarity to Gremlin in terms of promoter structure and predicted microRNA binding elements. This led us to discover that transforming growth factor-beta (TGFbeta1), a primary driver of cellular changes in the kidney during nephropathy, increased Gremlin, Jagged1 and Hes1 expression in human kidney epithelial cells. Elevated levels of Gremlin, Jagged1 and Hes1 were also detected in extracts from renal biopsies from diabetic nephropathy patients, but not in control living donors. In situ hybridization identified specific upregulation and co-expression of Gremlin, Jagged1 and Hes1 in the same tubuli of kidneys from diabetic nephropathy patients, but not controls. Finally, Notch pathway gene clustering showed that samples from diabetic nephropathy patients grouped together, distinct from both control living donors and patients with minimal change disease. Together, these data suggest that Notch pathway gene expression is elevated in diabetic nephropathy, co-incident with Gremlin, and may contribute to the pathogenesis of this disease.
Collections Ireland -> University College Dublin -> PubMed

Full list of authors on original publication

Finian Martin, Derek P. Brazil, Sergio Mezzano, Clemens D Cohen, Matthias Kretzler, Desmond G Higgins, Celine C Berthier, Paul McGettigan, Sarah A Roxburgh, David W Walsh

Experts in our system

1
Finian Martin
University College Dublin
Total Publications: 81
 
2
Derek P. Brazil
University College Dublin
Total Publications: 28
 
3
Desmond G Higgins
University College Dublin
Total Publications: 76
 
4
Paul A. McGettigan
University College Dublin
Total Publications: 46