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Genetic inhibition of discoidin domain receptor 1 protects mice against crescentic glomerulonephritis
Monique Kerroch1, Dominique Guerrot, Sophie Vandermeersch
1INSERM UMR S 702, Service de Néphrologie et Dialyses, Hôpital Tenon, Assistance Publique–Hôpitaux de Paris, Université Pierre et Marie Curie (UPMC), Paris 6 University, 75020 Paris, France.
Abstract:
This study investigated the role of discoidin domain receptor 1 (DDR1), a collagen receptor that displays tyrosine-kinase activity, in the development of glomerulonephritis. Crescentic glomerulonephritis was induced in DDR1-deficient mice and their wild-type (WT) littermates as controls, by injection of alloimmune sheep nephrotoxic serum (NTS). Histological, functional and transcriptomic studies were performed. Glomerulonephritis produced a 17-fold increase of DDR1 expression, predominantly in glomeruli. DDR1 deletion protected NTS-treated mice against glomerular disease (proteinuria/creatininuria 5.5±1.1 vs. 13.2±0.8 g/mmol in WT, crescents 12±2 vs. 24±2% of glomeruli, urea 16±2 vs. 28±5 mM), hypertension (123±11 vs. 157±8 mmHg), and premature death (70 vs. 10% survival) (all P<0.05). Reciprocal stimulation between DDR1 and interleukin-1b expression in vivo and in cultured podocytes suggested a positive feed-back loop between DDR1 and inflammation. In NTS-treated WT mice, administration of DDR1-specific antisense oligodeoxynucleotides decreased DDR1 expression (-56%) and protected renal function and structure, including nephrin expression (4.2±1.4 vs. 0.9±0.4 arbitrary units, P<0.05), compared to control mice receiving scrambled oligodeoxynucleotides. The therapeutic potential of this approach was reinforced by the observation of increased DDR1 expression in glomeruli of patients with lupus nephritis and Goodpasture's syndrome. These results prompt further interest in DDR1 blockade strategies, especially in the treatment of glomerulonephritis.
Insights
Discoidin domain receptor 1 (DDR1) plays a key role in glomerulonephritis development. Blocking DDR1 protects kidney function and structure, offering potential therapeutic strategies for kidney disease.
Area of Science:
- Nephrology
- Molecular Biology
- Immunology
Background:
- Discoidin domain receptor 1 (DDR1) is a tyrosine-kinase collagen receptor.
- Its role in glomerulonephritis pathogenesis is not well understood.
Purpose of the Study:
- To investigate the role of DDR1 in the development of glomerulonephritis.
- To explore DDR1 as a potential therapeutic target for kidney disease.
Main Methods:
- Induction of crescentic glomerulonephritis in DDR1-deficient and wild-type mice using nephrotoxic serum (NTS).
- Histological, functional, and transcriptomic analyses were performed.
- Administration of DDR1-specific antisense oligodeoxynucleotides in NTS-treated mice.
Main Results:
- Glomerulonephritis significantly increased DDR1 expression in glomeruli.
- DDR1 deficiency protected mice from glomerular disease, hypertension, and premature death.
- A positive feedback loop between DDR1 and interleukin-1b was observed.
- DDR1 blockade with antisense oligodeoxynucleotides improved renal function and structure, preserving nephrin expression.
- Elevated DDR1 expression was found in human lupus nephritis and Goodpasture's syndrome.
Conclusions:
- DDR1 is a critical mediator in glomerulonephritis development.
- Targeting DDR1 offers a promising therapeutic strategy for treating glomerulonephritis and related kidney diseases.
