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Gremlin and renal diseases: ready to jump the fence to clinical utility?
Sergio Mezzano1, Alejandra Droguett1, Carolina Lavoz1
1Division of Nephrology, School of Medicine, Universidad Austral de Chile, Valdivia, Chile.
Abstract:
The current therapeutic strategy for the treatment of chronic kidney diseases only ameliorates disease progression. During renal injury, developmental genes are re-expressed and could be potential therapeutic targets. Among those genes reactivated in the adult damaged kidney, Gremlin is of particular relevance since recent data suggest that it could be a mediator of diabetic nephropathy and other progressive renal diseases. Earlier studies have shown that Gremlin is upregulated in trans-differentiated renal proximal tubular cells and in several chronic kidney diseases associated with fibrosis. However, not much was known about the mechanisms by which Gremlin acts in renal pathophysiology. The role of Gremlin as a bone morphogenetic protein antagonist has clearly been demonstrated in organogenesis and in fibrotic-related disorders. Gremlin binds to vascular endothelial growth factor receptor 2 (VEGFR2) in endothelial and tubular epithelial cells. Activation of the Gremlin-VEGFR2 axis was found in several human nephropathies. We have recently described that Gremlin activates the VEGFR2 signaling pathway in the kidney, eliciting a downstream mechanism linked to renal inflammatory response. Gremlin deletion improves experimental renal damage, diminishing fibrosis. Overall, the available data identify the Gremlin-VEGFR2 axis as a novel therapeutic target for kidney inflammation and fibrosis and provide a rationale for unveiling new concepts to investigate in several clinical conditions.
Insights
Gremlin, a developmental gene reactivated during kidney injury, promotes inflammation and fibrosis by activating the Gremlin-VEGFR2 axis. Targeting this pathway offers a novel therapeutic strategy for chronic kidney diseases.
Area of Science:
- Nephrology
- Molecular Biology
- Developmental Biology
Background:
- Current chronic kidney disease (CKD) treatments only slow progression.
- Developmental genes, like Gremlin, are reactivated during renal injury and present potential therapeutic targets.
- Gremlin's role as a bone morphogenetic protein antagonist and its upregulation in fibrotic CKD are known, but its precise mechanisms in renal pathophysiology were unclear.
Purpose of the Study:
- To investigate the mechanisms by which Gremlin contributes to renal pathophysiology.
- To explore the role of the Gremlin-VEGFR2 axis in kidney inflammation and fibrosis.
- To evaluate Gremlin deletion as a potential therapeutic strategy for experimental renal damage.
Main Methods:
- Analysis of Gremlin expression in trans-differentiated renal proximal tubular cells and in various CKD models.
- Investigating Gremlin's interaction with vascular endothelial growth factor receptor 2 (VEGFR2) in kidney cells.
- Studying the downstream signaling pathways activated by the Gremlin-VEGFR2 axis.
- Assessing the effects of Gremlin deletion on experimental renal damage and fibrosis.
Main Results:
- Gremlin is upregulated in specific renal cell types and conditions associated with CKD.
- Gremlin directly binds to VEGFR2 in endothelial and tubular epithelial cells, forming an axis activated in human nephropathies.
- Activation of the Gremlin-VEGFR2 axis triggers downstream signaling leading to renal inflammation.
- Gremlin deletion significantly ameliorates experimental renal damage and reduces fibrosis.
Conclusions:
- The Gremlin-VEGFR2 axis is a key mediator of kidney inflammation and fibrosis.
- Targeting the Gremlin-VEGFR2 axis represents a novel therapeutic strategy for progressive kidney diseases.
- Further research into this axis may unveil new therapeutic concepts for various clinical conditions affecting the kidney.
