Chronic Treatment with the Direct AMPK Activator PXL770 Improves Cardiac, Vascular, and Renal Function in Rodents with Diabetes-Related Cardiorenal Disease

Introduction: PXL770 is a direct AMP kinase activator. In models of T2DM and NASH, PXL770 improves hyperglycemia and dyslipidemia and reduces: steatosis, inflammation, fibrogenesis. Whether these beneficial effects are associated with an improvement in diabetes-related cardiac, vascular and renal dysfunctions is unknown. Methods: Diabetic ZSF-1 rats were treated for 90 days with PXL770 (150 mg/kg BID), then cardiac function (left ventricular (LV) hemodynamics), in vitro flow-mediated dilation (FMD; arteriograph) of mesenteric artery, renal histology and function (transcutaneous GFR) were assessed. Results: Untreated ZSF-1 rats exhibited LV diastolic dysfunction, i.e., increases in LV End-Diastolic Pressure (LVEDP; 8.3±1.0 vs. 5.6±0.6 mm Hg in lean, p<.05) and LV End-Diastolic Pressure Volume Relation (LVEDPVR; 5.4±0.6 vs. 1.1±0.2 mm Hg/RVU in lean, p<.05). Myocardial tissue perfusion was reduced (4.0±0.2 vs. 7.4±0.9 ml/min/g in lean, p<.05). Untreated rats exhibited impaired mesenteric FMD (% of preconstriction; 37±11 vs. 70±7% in lean, p<.05) and renal function and structure as shown by a reduction in GFR (4.4±0.5 vs. 5.6±0.5 ml/min in lean, p<.05) and increase in glomerular score (2.3±0.2 vs. 0.6±0.1 AU in lean, p<.05). Compared to untreated ZSF-1 rats, 90-day PXL770 reduced glycaemia (-31 %, p<.05) and plasma triglycerides (-44 %, p<.05). PXL770 decreased LVEDP (-28 %) and LVEDPVR (2.7±0.2 mm Hg/RVU, p<.05) and increased LV tissue perfusion (+30 %, p<.05). PXL770 improved mesenteric FMD (64±3%, p<.05) and increased GFR (6.0±0.1 ml/min, p<.05) and reduced glomerular score (1.6±0.2, p<.05). Conclusion: In ZSF-1 rats, improvement of metabolic status induced by long-term treatment with the AMP kinase activator PXL770 is associated with an improved LV diastolic, vascular and renal function/structure. PXL770 could have therapeutic utility for the treatment of metabolic diseases and related co-morbid conditions. Disclosure Y. Stephan: None. M. Soulié: None. L. Nicol: None. P. Gluais-dagorn: Employee; Self; Poxel SA. S. Hallakou-bozec: None. P. Mulder: None. Funding Poxel SA