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The non-steroidal mineralocorticoid receptor antagonist (MRA) finerenone (FIN) improves kidney and cardiovascular outcomes in patients with chronic kidney disease (CKD) in type 2 diabetes (T2D). We explored the effect of FIN in a novel model of type 1 diabetic Munich Wistar Frömter (MWF) rat (D) induced by injection of streptozotocin (15 mg/kg) and additional exposure to a high-fat/high-sucrose diet. Oral treatment with FIN (10 mg/kg/day in rat chow) in diabetic animals (D -FIN) was compared to a group of D rats receiving no treatment and a group of non-diabetic untreated MWF rats (C) (n = 7–10 animals per group). After 6 weeks, D and D -FIN exhibited significantly elevated blood glucose levels (271.7 ± 67.1 mg/dl and 266.3 ± 46.8 mg/dl) as compared to C (110.3 ± 4.4 mg/dl; p < 0.05). D showed a 10-fold increase of kidney damage markers Kim-1 and Ngal which was significantly suppressed in D -FIN. Blood pressure, pulse wave velocity (PWV) and arterial collagen deposition were lower in D -FIN, associated to an improvement in endothelial function due to a reduction in pro-contractile prostaglandins, as well as reactive oxygen species (ROS) and inflammatory cytokines (IL-1, IL-6, TNFα and TGFβ) in perivascular and perirenal adipose tissue (PVAT and PRAT, respectively). In addition, FIN restored the imbalance observed in CKD between the procalcifying BMP-2 and the nephroprotective BMP-7 in plasma, kidney, PVAT, and PRAT. Our data show that treatment with FIN improves kidney and vascular damage in a new rat model of DKD with T1D associated with a reduction in inflammation, fibrosis and osteogenic factors independently from changes in glucose homeostasis. [Display omitted] • FIN has a protective effect on kidney and cardiovascular damage progression in a new model of T1DM in established CKD. • FIN reduces kidney damage markers, blood pressure, vascular prostanoids, ROS and collagen content, PWV and heart weight. • FIN prevents diabetes-induced upregulation of proinflammatory, profibrotic, and osteogenic factors in PVAT and PRAT. • FIN restores the imbalance between procalcifying BMP-2 and nephroprotective BMP-7 in plasma, kidney, PVAT, and PRAT. • All beneficial effects of FIN are observed despite no change in glycaemia or other characteristic symptoms of diabetes. • These results support further studies exploring the therapeutic potential of FIN on kidney and vascular damage in T1DM. [ABSTRACT FROM AUTHOR]

The key for the survival of all organisms is the regulation and control of energy metabolism. Thus, several strategies have evolved in each tissue in order to balance nutrient supply with energy demand. Adenosine monophosphate-activated protein kinase (AMPK) is now recognized as a key participant in energy metabolism. It ensures an appropriate energetic supply by promoting energy conserving pathways in detriment of anabolic processes not essential for cell survival. Vascular AMPK plays a critical role in the regulation of blood flow and vascular tone through several mechanisms, including vasodilation by stimulating nitric oxide release in endothelial cells. Since obesity leads to endothelial damage and AMPK dysregulation, AMPK activation might be an important strategy to restore vascular function in cardiometabolic alterations. In the present review we focus on the role of vascular AMPK in both endothelial and smooth muscle cells, paying special attention to its dysregulation in obesity- and high-fat diet-related complications, as well as to the mechanisms and benefits of vascular AMPK activation. [ABSTRACT FROM AUTHOR]

Genetic obesity models exhibit endothelial dysfunction associated to adenosine monophosphate-activated protein kinase (AMPK) dysregulation. This study aims to assess if mild short-term caloric restriction (CR) restores endothelial AMPK activity leading to an improvement in endothelial function. Twelve-week old Zucker lean and obese (fa/fa) male rats had access to standard chow either ad libitum (AL, n = 8) or 80% of AL (CR, n = 8) for two weeks. Systolic blood pressure was significantly higher in fa/fa AL rats versus lean AL animals, but was normalized by CR. Endothelium-dependent relaxation to acetylcholine (ACh, 10-9 to 10-4 M) was reduced in fa/fa AL compared to control lean AL rats (p < 0.001), and restored by CR. The AMPK activator AICAR (10-5 to 8·10-3 M) elicited a lower relaxation in fa/fa AL rings that was normalized by CR (p < 0.001). Inhibition of PI3K (wortmannin, 10-7 M), Akt (triciribine, 10-5 M), or eNOS (L-NAME, 10-4 M) markedly reduced AICAR-induced relaxation in lean AL, but not in fa/fa AL rats. These inhibitions were restored by CR in Zucker fa/fa rings. These data show that mild short-term CR improves endothelial function and lowers blood pressure in obesity due to the activation of the AMPK-PI3K-Akt-eNOS pathway. [ABSTRACT FROM AUTHOR]