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

Diana Rubel,Michelle Callahan,Ethan Y Xu,Hervé Husson,Wenping Song,Oliver Gross,Nikolay O Bukanov,Shiguang Liu,William Weber,Xingyi Shi,Ali Hariri,Florin Craciun,Oxana Ibraghimov-Beskrovnaya,Lucy Phillips,Nicholas Ngai,Joseph Boulanger,Yanqin Zhang

doi:10.3390/cells11040594

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.

Highlights

Alport syndrome (AS) is a hereditary disorder characterized by mutations in the genes encoding for the α3, α4 or α5 chain of type IV collagen, leading to defective glomerular basement membranes (GBMs)
AS recently has become a treatable disease, as renal failure can be delayed by years and life expectancy improved by angiotensinconverting enzyme inhibitors (ACEi) [10–12]
Our experiments demonstrated that human patients with AS and progressive disease despite RAAS blockade may benefit from anti-miR-21 therapy in addition to high-dose

Summary

Introduction

Alport syndrome (AS) is a hereditary disorder characterized by mutations in the genes encoding for the α3, α4 or α5 chain of type IV collagen, leading to defective glomerular basement membranes (GBMs). In the course of the disease, the thickening and splitting of the GBM are accompanied by hematuria, proteinuria and progressive renal fibrosis leading to end-stage renal failure [1,2]. Several animal models of AS have been established, one of which is the Col4a3−/−. Mouse model introduced by Cosgrove and colleagues [3]. Several treatments, including renin–angiotensin–aldosterone-system (RAAS) blockade, stem cells and anti-fibrotic therapy, have been evaluated in this model [4–9]. AS recently has become a treatable disease, as renal failure can be delayed by years and life expectancy improved by angiotensinconverting enzyme inhibitors (ACEi) [10–12]. New therapies beyond RAAS blockade are strongly needed to further delay renal fibrosis in AS [13]. −/− mice with chronic chronic kidney disease. 129/SvJbackground background was was 10 weeks (Figure S1). The median survival with survival time time of ofvehicle-treated vehicle-treatedCol4a3

Methods

Discussion

Conclusion