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Published on: April 21, 2015
Deletion of delta-like 1 homologue accelerates renal inflammation by modulating the Th17 immune response
Laura Marquez-Exposito1,2, Raul R Rodrigues-Diez1,2, Sandra Rayego-Mateos1,3
1Cellular and Molecular Biology in Renal and Vascular Pathology, IIS-Fundación Jiménez Díaz. Universidad Autónoma de Madrid, Madrid, Spain.
Abstract:
Preclinical studies have demonstrated that activation of the NOTCH pathway plays a key role in the pathogenesis of kidney damage. There is currently no information on the role of the Delta-like homologue 1 (DLK1), a NOTCH inhibitor, in the regulation of renal damage. Here, we investigated the contribution of DLK1 to experimental renal damage and the underlying molecular mechanisms. Using a Dlk1-null mouse model in the experimental renal damage of unilateral ureteral obstruction, we found activation of NOTCH, as shown by increased nuclear translocation of the NOTCH1 intracellular domain, and upregulation of Dlk2/hey-1 expression compared to wild-type (WT) littermates. NOTCH1 over-activation in Dlk1-null injured kidneys was associated with a higher inflammatory response, characterized by infiltration of inflammatory cells, mainly CD4/IL17A + lymphocytes, and activation of the Th17 immune response. Furthermore, pharmacological NOTCH blockade inhibited the transcription factors controlling Th17 differentiation and gene expression of the Th17 effector cytokine IL-17A and other related-inflammatory factors, linked to a diminution of inflammation in the injured kidneys. We propose that the non-canonical NOTCH ligand DLK1 acts as a NOTCH antagonist in renal injury regulating the Th17-mediated inflammatory response.
Insights
Delta-like homologue 1 (DLK1) inhibits NOTCH signaling, reducing kidney inflammation and Th17 immune responses in experimental renal damage. DLK1 acts as a NOTCH antagonist, protecting against kidney injury.
Area of Science:
- Nephrology
- Immunology
- Molecular Biology
Background:
- NOTCH pathway activation contributes to kidney damage pathogenesis.
- The role of Delta-like homologue 1 (DLK1), a NOTCH inhibitor, in renal damage is unknown.
Purpose of the Study:
- To investigate DLK1's contribution to experimental renal damage.
- To elucidate the molecular mechanisms underlying DLK1's role in kidney injury.
Main Methods:
- Utilized a Dlk1-null mouse model for unilateral ureteral obstruction (UUO) induced renal damage.
- Assessed NOTCH pathway activation via NOTCH1 intracellular domain translocation and Dlk2/hey-1 expression.
- Analyzed inflammatory response, including immune cell infiltration and Th17 pathway activation.
- Employed pharmacological NOTCH blockade to evaluate its impact on inflammation.
Main Results:
- Dlk1-null mice exhibited increased NOTCH activation and Dlk2/hey-1 expression post-UUO compared to wild-type littermates.
- NOTCH1 over-activation in Dlk1-null kidneys correlated with heightened inflammation and Th17 immune response.
- Pharmacological NOTCH blockade reduced Th17 differentiation, IL-17A expression, and kidney inflammation.
Conclusions:
- DLK1 functions as a non-canonical NOTCH antagonist in renal injury.
- DLK1 regulates the Th17-mediated inflammatory response in experimental kidney damage.
- Targeting DLK1 may offer a therapeutic strategy for kidney diseases involving NOTCH signaling.
