Abstract P3094: Mir-181c-5p As Detrimental Player In A Mouse Model Of Cardiorenal Syndrome With Thrombotic Microangiopathy

• Published in: Circulation research 2022-08, Vol.131 (Suppl_1), p.AP3094-AP3094
• Main Authors: Boen, Jente R, Krüger, Dustin, Dendooven, Amélie, Bruyns, Tine, Van Fraeyenhove, Jens, Feyen, Eline, Gevaert, Andreas B, Segers, Vincent F, Van Craenenbroeck, Emeline M
• Format: Article
• Language: English
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/res.131.suppl_1.P3094

BackgroundMiR-181c-5p is described to induce heart failure (HF), while its role in renal pathology is undetermined. Renal dysfunction is present in 40-60% of HF patients and associated with poor prognosis. This study is the first of its kind to investigate the role of miR-181c-5p in a mouse model of cardiorenal disease (CRD). Our hypothesis states a protective effect of miR-181c-5p inhibition on HF development. MethodsCRD was induced by feeding male C57BL/6J mice (n=20) a high-fat diet (HFD) and L-NAME in drinking water (5g/L) for 6 weeks, angiotensin-II was co-administered via osmotic minipumps (1000ng/kg/min) during the final 2 weeks. Healthy controls (n=16) underwent sham-surgery. Mice were randomly assigned to weekly injections (40mg/kg) with miR-181c-5p antagomiR (INH) or scrambled control for the duration of the study. We assessed cardiac function (echocardiography, hemodynamics), renal function (plasma creatinine), target expression (RT-qPCR), and histology. ResultsCRD animals showed mild systolic and diastolic cardiac dysfunction compared to healthy controls, with cardiac fibrosis (2.5±0.3 vs 1.8±0.2% area; p=0.0004) and hypertrophy (0.11±0.03 vs 0.08±0.01g/cm; p=0.005). Renal dysfunction presents with kidney atrophy (0.07±0.006 vs 0.09±0.01g/cm; p=0.02), increased plasma creatinine (21±6 vs 10±5; p=0.01), renal fibrosis (0.26±0.22 vs 0.005±0.21 % area; p=0.036) and glomerular abnormalities (glomerulosclerosis, hypertrophy/atrophy, mesangial matrix expansion, reduced podocyte number). CRD+INH animals had comparable cardiac phenotype to CRD (p>0.05). Their renal phenotype was exacerbated with elevated glomerular damage (26±3 vs 18±9;p=0.04) and significantly increased mortality rate (50%) (Kaplan-Meier p=0.01) compared to healthy controls (0%) or CRD (20%), associated with increased occurrence of tubular atrophy, endothelial swelling and systemic thrombotic microangiopathy (TMA). qPCR analysis identified Vegf as potential target of miR-181c-5p. ConclusionThis study demonstrates a detrimental effect of miR-181c-5p inhibition on renal function in a CRD mouse model, driven by glomerular damage and TMA through Vegf signaling. Cardiac function was unaffected.