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Cardiotrophin-1 therapy reduces disease severity in a murine model of glomerular disease
Nuria Perretta-Tejedor1,2,3, Karen L Price1,2, Daniyal J Jafree1,2,4
1Developmental Biology and Cancer Research and Teaching Department, UCL Great Ormond Street Institute of Child Health, London, UK.
Insights
Cardiotrophin-1 (CT-1) protects against glomerular disease progression in mice. CT-1 therapy reduced kidney damage, inflammation, and fibrosis, highlighting its therapeutic potential for kidney diseases.
Area of Science:
- Nephrology
- Immunology
- Molecular Biology
Background:
- Cardiotrophin-1 (CT-1), an IL-6 family cytokine, shows renoprotective effects in kidney injury models.
- The role of CT-1 in immune-mediated glomerular diseases remains uncharacterized.
Purpose of the Study:
- To investigate the role of CT-1 in immune-mediated glomerular disease using a mouse model.
- To determine if CT-1 exhibits protective effects in established glomerular injury.
Main Methods:
- Utilized the nephrotoxic nephritis mouse model.
- Assessed CT-1 expression via immunohistochemistry and single-cell RNA-sequencing in isolated glomeruli.
- Administered CT-1 to mice with established proteinuria and analyzed kidney function, podocyte loss, inflammation, and fibrosis.
Main Results:
- CT-1 is expressed in mouse glomeruli, primarily in parietal epithelial cells, and is downregulated during nephrotoxic nephritis.
- Reduced glomerular CT-1 transcript levels were observed in human glomerular disease patients.
- CT-1 treatment in mice reduced albuminuria, prevented podocyte loss, stabilized plasma creatinine, decreased cortical fibrosis, and lowered peri-glomerular macrophage accumulation and complement component 5a levels.
Conclusions:
- CT-1 plays a protective role in immune-mediated glomerular disease.
- CT-1 intervention therapy can delay glomerular disease progression by preserving kidney function and reducing renal inflammation and fibrosis.
Abstract:
Cardiotrophin-1 (CT-1), a member of the interleukin (IL)-6 cytokine family, has renoprotective effects in mouse models of acute kidney disease and tubulointerstitial fibrosis, but its role in glomerular disease is unknown. To address this, we used the mouse model of nephrotoxic nephritis to test the hypothesis that CT-1 also has a protective role in immune-mediated glomerular disease. Using immunohistochemistry and analysis of single-cell RNA-sequencing data of isolated glomeruli, we demonstrate that CT-1 is expressed in the glomerulus in male mice, predominantly in parietal epithelial cells and is downregulated in mice with nephrotoxic nephritis. Furthermore, analysis of data from patients revealed that human glomerular disease is also associated with reduced glomerular CT-1 transcript levels. In male mice with nephrotoxic nephritis and established proteinuria, administration of CT-1 resulted in reduced albuminuria, prevented podocyte loss, and sustained plasma creatinine, compared with mice administered saline. CT-1 treatment also reduced fibrosis in the kidney cortex, peri-glomerular macrophage accumulation and the kidney levels of the pro-inflammatory mediator complement component 5a. In conclusion, CT-1 intervention therapy delays the progression of glomerular disease in mice by preserving kidney function and inhibiting renal inflammation and fibrosis.
