Anti-microRNA-21 Therapy on Top of ACE Inhibition Delays Renal Failure in Alport Syndrome Mouse Models.

Abstract

Col4a3-/- Alport mice serve as an animal model for renal fibrosis. MicroRNA-21 (miR-21) expression has been shown to be increased in the kidneys of Alport syndrome patients. Here, we investigated the nephroprotective effects of Lademirsen anti-miR-21 therapy. We used a fast-progressing Col4a3-/- mouse model with a 129/SvJ background and an intermediate-progressing F1 hybrid mouse model with a mixed genetic background, with angiotensin-converting enzyme inhibitor (ACEi) monotherapy in combination with anti-miR-21 therapy. In the fast-progressing model, the anti miR-21 and ACEi therapies showed an additive effect in the reduction in fibrosis, the decline of proteinuria, the preservation of kidney function and increased survival. In the intermediate-progressing F1 model, the anti-miR-21 and ACEi therapies individually improved kidney pathology. Both also improved kidney function and survival; however, the combination showed a significant additive effect, particularly for survival. RNA sequencing (RNA-seq) gene expression profiling revealed that the anti-miR-21 and ACEi therapies modulate several common pathways. However, anti-miR-21 was particularly effective at normalizing the expression profiles of the genes involved in renal tubulointerstitial injury pathways. In conclusion, significant additive effects were detected for the combination of anti-miR-21 and ACEi therapies on kidney function, pathology and survival in Alport mouse models, as well as a strong differential effect of anti-miR-21 on the renal expression of fibrotic factors. These results support the addition of anti-miR-21 to the current standard of care (ACEi) in ongoing clinical trials in patients with Alport syndrome.

• Authors: Diana Rubel, Joseph Boulanger, Florin Craciun, Ethan Y Xu, Yanqin Zhang, Lucy Phillips, Michelle Callahan, William Weber, Wenping Song, Nicholas Ngai, Nikolay O Bukanov, Xingyi Shi, Ali Hariri, Hervé Husson, Oxana Ibraghimov-Beskrovnaya, Shiguang Liu, Oliver Gross
• Journal: Cells (Cells) Vol. 11 Issue 4 (02 09 2022) ISSN: 2073-4409 [Electronic] Switzerland
• PMID: 35203245 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Angiotensin-Converting Enzyme Inhibitors
• Antagomirs
• Collagen Type IV
• MIRN21 microRNA, mouse
• MicroRNAs

Topics

• Angiotensin-Converting Enzyme Inhibitors (pharmacology)
• Animals
• Antagomirs
• Collagen Type IV (genetics, metabolism)
• Disease Models, Animal
• Fibrosis
• Humans
• Mice
• Mice, Knockout
• MicroRNAs (antagonists & inhibitors)
• Nephritis, Hereditary (drug therapy, genetics)
• Renal Insufficiency (drug therapy)