FINERENONE PREVENTS RENAL AND VASCULAR DAMAGE IN A NOVEL MODEL OF TYPE 1 DIABETES MELLITUS

Abstract

The non-steroidal mineralocorticoid receptor antagonist (MRA), finerenone (FIN) improves renal and cardiovascular outcomes in patients with chronic kidney disease (CKD) in type 2 diabetes (T2D). We explored the effects of FIN in a novel model of CKD in type 1 diabetes (T1D).We employed the Munich Wistar Frömter (MWF) rat model of non-diabetic CKD with mild hypertension and albuminuria to generate a novel model of CKD with T1D. This was achieved by an intra-peritoneal 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 (MWF-DKD-FIN) was compared to a group of diabetic rats receiving no treatment (MWF-DKD-Control) and a group of non-diabetic untreated MWF rats (MWF). Dietary exposure with or without pharmacological treatment was maintained for 6 weeks (n = 7-10 animals per group).After 6 weeks, MWF-DKD-Control and MWF-DKD-FIN exhibited significantly elevated blood glucose levels (271.7 ± 67.1 mg/dl and 266.3 ± 46.8 mg/dl) as compared to MWF (110.3 ± 4.4 mg/dl; p < 0.05). MWF-DKD-Control showed a 10-fold higher expression of renal damage markers Kim-1 and Ngal compared to MWF. This upregulation was significantly suppressed in MWF-DKD-FIN. FIN treatment resulted in a significant reduction of blood pressure and pulse wave velocity compared to MWF-DKD-Control (p < 0.05). Vascular function studies showed an improvement in endothelial function in MWF-DKD-FIN compared to MWF-DKD-Control due to a reduction in pro-contractile prostaglandins, oxidative stress, and inflammatory cytokines (including IL-1, IL-6, TNFalpha and TGFbeta). FIN induced no changes in blood glucose levels, glucose tolerance or the increase in HOMA index compared to MWF-DKD-Control.Our data show that treatment with FIN improves renal and vascular damage in a new rat model of CKD with T1D. These beneficial effects associated with a reduction in inflammation and oxidative stress and was independent from changes in glucose homeostasis.