Anti-microRNA-21 Therapy on Top of ACE Inhibition Delays Renal Failure in Alport Syndrome Mouse Models
<i>Col4a3<sup>−/−</sup></i> 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...
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MDPI AG
2022-02-01
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| author | 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 |
| author_facet | 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 |
| author_sort | Diana Rubel |
| collection | DOAJ |
| description | <i>Col4a3<sup>−/−</sup></i> 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 <i>Col4a3<sup>−/−</sup></i> 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. |
| first_indexed | 2024-03-09T22:21:30Z |
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| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-09T22:21:30Z |
| publishDate | 2022-02-01 |
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| spelling | doaj.art-c718a14f7c9d4c8e9cc449aec48ae2ec2023-11-23T19:13:47ZengMDPI AGCells2073-44092022-02-0111459410.3390/cells11040594Anti-microRNA-21 Therapy on Top of ACE Inhibition Delays Renal Failure in Alport Syndrome Mouse ModelsDiana Rubel0Joseph Boulanger1Florin Craciun2Ethan Y. Xu3Yanqin Zhang4Lucy Phillips5Michelle Callahan6William Weber7Wenping Song8Nicholas Ngai9Nikolay O. Bukanov10Xingyi Shi11Ali Hariri12Hervé Husson13Oxana Ibraghimov-Beskrovnaya14Shiguang Liu15Oliver Gross16Clinic for Nephrology and Rheumatology, University Medical Center Goettingen, 37075 Goettingen, GermanySanofi Research & Development, Cambridge, MA 02142, USASanofi-Genzyme Research and Development, Framingham, MA 02118, USASanofi-Genzyme Research and Development, Framingham, MA 02118, USAClinic for Nephrology and Rheumatology, University Medical Center Goettingen, 37075 Goettingen, GermanySanofi-Genzyme Research and Development, Framingham, MA 02118, USASanofi-Genzyme Research and Development, Framingham, MA 02118, USASanofi-Genzyme Research and Development, Framingham, MA 02118, USASanofi-Genzyme Research and Development, Framingham, MA 02118, USASanofi-Genzyme Research and Development, Framingham, MA 02118, USASanofi-Genzyme Research and Development, Framingham, MA 02118, USASanofi-Genzyme Research and Development, Framingham, MA 02118, USASanofi-Genzyme, Clinical Development, Cambridge, MA 02142, USASanofi-Genzyme Research and Development, Framingham, MA 02118, USASanofi-Genzyme Research and Development, Framingham, MA 02118, USASanofi-Genzyme, Clinical Development, Cambridge, MA 02142, USAClinic for Nephrology and Rheumatology, University Medical Center Goettingen, 37075 Goettingen, Germany<i>Col4a3<sup>−/−</sup></i> 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 <i>Col4a3<sup>−/−</sup></i> 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.https://www.mdpi.com/2073-4409/11/4/594nephroprotectionrenal fibrosistype IV collagenAlport syndromemicroRNA-21podocytopathies |
| spellingShingle | 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 Anti-microRNA-21 Therapy on Top of ACE Inhibition Delays Renal Failure in Alport Syndrome Mouse Models Cells nephroprotection renal fibrosis type IV collagen Alport syndrome microRNA-21 podocytopathies |
| title | Anti-microRNA-21 Therapy on Top of ACE Inhibition Delays Renal Failure in Alport Syndrome Mouse Models |
| title_full | Anti-microRNA-21 Therapy on Top of ACE Inhibition Delays Renal Failure in Alport Syndrome Mouse Models |
| title_fullStr | Anti-microRNA-21 Therapy on Top of ACE Inhibition Delays Renal Failure in Alport Syndrome Mouse Models |
| title_full_unstemmed | Anti-microRNA-21 Therapy on Top of ACE Inhibition Delays Renal Failure in Alport Syndrome Mouse Models |
| title_short | Anti-microRNA-21 Therapy on Top of ACE Inhibition Delays Renal Failure in Alport Syndrome Mouse Models |
| title_sort | anti microrna 21 therapy on top of ace inhibition delays renal failure in alport syndrome mouse models |
| topic | nephroprotection renal fibrosis type IV collagen Alport syndrome microRNA-21 podocytopathies |
| url | https://www.mdpi.com/2073-4409/11/4/594 |
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