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

• Published in: Cells (Basel, Switzerland) Vol. 11; no. 4; p. 594
• Main 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
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 09.02.2022; MDPI
• Subjects: Age; Alport syndrome; Angiotensin; Angiotensin-converting enzyme inhibitors; Angiotensin-Converting Enzyme Inhibitors - pharmacology; Animal models; Animals; Antagomirs; Antibodies; Clinical trials; Collagen Type IV - genetics; Collagen Type IV - metabolism; Disease; Disease Models, Animal; Drinking water; Fibrosis; Gene expression; Humans; Kidneys; Metabolism; Mice; Mice, Knockout; microRNA-21; MicroRNAs; MicroRNAs - antagonists & inhibitors; miRNA; Nephritis, Hereditary - drug therapy; Nephritis, Hereditary - genetics; nephroprotection; Pathology; Patients; Peptidyl-dipeptidase A; podocytopathies; Proteinuria; Renal failure; renal fibrosis; Renal Insufficiency - drug therapy; Survival; type IV collagen; United States > US; Germany; Alport syndrome; hereditary kidney diseases; type IV collagen; podocytopathies; kidney therapies; nephroprotection; renal fibrosis; microRNA-21
• ISSN: 2073-4409; 2073-4409
• DOI: 10.3390/cells11040594

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 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.