Abstract P087: Metformin Treatment Decreases Blood Pressure But Does Not Ameliorate Hypertensive Cardio-Renal Damage In A Double Transgenic Rat Model

Abstract

Introduction: Metformin (Met) is used as a first-line treatment in type II diabetes, reduces the cardiovascular (CV) risk in diabetes and may lead to decreased CV mortality independent of diabetes status. Met treatment has been shown to induce gut microbiome changes leading to enhanced production of protective short-chain fatty acids and potentially harmful metabolites (LPS). Our study aims to examine the effects of Met in a model of RAAS-mediated hypertension with cardio-renal damage. Methods: Four-week-old double transgenic rats (dTGR, transgenic for human renin and angiotensinogen) received oral Metformin (Met) or Vehicle (Veh) for 3 weeks. SD rats served as healthy controls. Flow cytometry (n=10 per group), echocardiography (n=14), radiotelemetric blood pressure (BP) measurements (n=5), clinical chemistry and gene expression analyses (n=14) were used to assess damage to kidney and heart. Results: Met treatment did not influence survival nor lead to lactate acidosis. Met treatment lowered BP significantly (systolic BP: Met: 218±5 mmHg, Veh: 237±3 mmHg). Interestingly, the decreased BP was accompanied by increased cardiac hypertrophy (heart weight to tibia length, SD: 34±1 g/m, Met: 40±1 g/m, Veh: 37±1 g/m). Echocardiographic systolic and diastolic function was deteriorated (EF: Met: 64±2 %, Veh: 68±4 %; E/A: Met: 0.75±0.1, Veh: 0.93±0.1). Plasma BNP and cardiac ß-to-α MHC ratio were higher in Met-treated dTGR. Intestines, spleens, kidneys and hearts of dTGR showed a strong pro-inflammatory phenotype with increased adaptive (e.g. cardiac T cells % of leucocytes: (SD: 10±0.003 %, Met: 15±0.01 %, Veh: 13±0.01 %) and innate (e.g. cardiac monocytes % of leucocytes: (SD: 2±0.001 %, Met: 3±0.004 %, Veh: 5±0.02 %) immune cell subsets in comparison to SD rats; with almost no differences between Met- and Veh-treated dTGR. Fecal metagenomic shotgun sequencing showed no large-scale taxonomic shifts between Veh- and Met-treated dTGR. Conclusion: dTGR display a pronounced pro-inflammatory immunophenotype across several organs. Met did not ameliorate hypertensive target organ damage in dTGR despite the BP lowering effect. These findings could help to understand the effects of Met on the microbiome, immunome and organ damage in the context of hypertension.