Anti-microRNA-21 Therapy on Top of ACE Inhibition Delays Renal Failure in Alport Syndrome Mouse Models
| Autor: | 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 |
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| Rok vydání: | 2021 |
| Předmět: |
Collagen Type IV
Mice Knockout Antagomirs Angiotensin-Converting Enzyme Inhibitors Nephritis Hereditary General Medicine Fibrosis Disease Models Animal Mice MicroRNAs Animals Humans nephroprotection renal fibrosis type IV collagen Alport syndrome microRNA-21 podocytopathies hereditary kidney diseases kidney therapies Renal Insufficiency |
| Zdroj: | Cells; Volume 11; Issue 4; Pages: 594 |
| ISSN: | 2073-4409 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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