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- Title
Anti-microRNA-21 Therapy on Top of ACE Inhibition Delays Renal Failure in Alport Syndrome Mouse Models.
- Authors
Rubel, Diana; Boulanger, Joseph; Craciun, Florin; Xu, Ethan Y.; Zhang, Yanqin; Phillips, Lucy; Callahan, Michelle; Weber, William; Song, Wenping; Ngai, Nicholas; Bukanov, Nikolay O.; Shi, Xingyi; Hariri, Ali; Husson, Hervé; Ibraghimov-Beskrovnaya, Oxana; Liu, Shiguang; Gross, Oliver
- 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.
- Subjects
KIDNEY failure; LABORATORY mice; ANIMAL disease models; GENE expression profiling; RENAL fibrosis; ANGIOTENSIN converting enzyme; ANGIOTENSIN I
- Publication
Cells (2073-4409), 2022, Vol 11, Issue 4, p594
- ISSN
2073-4409
- Publication type
Article
- DOI
10.3390/cells11040594