Co-regulation of Gremlin and Notch signalling in diabetic nephropathy.
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.
Walsh
David W
DW
UCD School of Biomolecular and Biomedical Science, Conway Institute, University College Dublin, Belfield, Ireland.
Roxburgh
Sarah A
SA
McGettigan
Paul
P
Berthier
Celine C
CC
Higgins
Desmond G
DG
Kretzler
Matthias
M
Cohen
Clemens D
CD
Mezzano
Sergio
S
Brazil
Derek P
DP
Martin
Finian
F
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D001665:Binding Sites; D001706:Biopsy; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000235:genetics; D002460:Cell Line; D016207:Cytokines; D003928:Diabetic Nephropathies / Q000235:genetics / Q000378:metabolism*; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D000072100:Jagged-1 Protein; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D011401:Promoter Regions, Genetic / Q000235:genetics; D011506:Proteins; D051381:Rats; D051880:Receptors, Notch / Q000378:metabolism*; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology
D051792:Basic Helix-Loop-Helix Proteins; D019485:Bone Morphogenetic Proteins; D002135:Calcium-Binding Proteins; D016207:Cytokines; D036341:Intercellular Signaling Peptides and Proteins; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D011506:Proteins; D051880:Receptors, Notch; D000072099:Serrate-Jagged Proteins; D053773:Transforming Growth Factor beta1; C113178:Grem1 protein, mouse; C486399:GREM1 protein, human; C107276:Grem1 protein, rat; C000606273:JAG1 protein, human; C000606274:Jag1 protein, mouse; C000606275:Jag1 protein, rat