387-P: Finerenone Attenuates Kidney GLP-1 Receptor Downregulation in Mice with Comorbid Diabetes

Introduction & Objective: Several new treatments have recently been shown to have kidney protective benefits in people with diabetes. Because these treatments were developed in parallel, at the time of their clinical trial participation many individuals were not receiving concurrent treatment with other therapies subsequently also found to have kidney protective benefits. Accordingly, it is unclear whether treatments recently shown to slow kidney function decline will have additive or redundant effects when used in combination. Here, we examined the effects of the mineralocorticoid receptor antagonist finerenone on kidney GLP-1 receptor (GLP-1R) expression levels in mice with comorbid diabetes.

Methods: Mice were fed a high fat diet and received a single intraperitoneal injection of streptozotocin 12 weeks into high fat diet feeding (DM-HFD mice). After 24 weeks, animals were fed high fat diet containing finerenone (100mg/kg diet) for a further 2 weeks. Kidney GLP-1R localization and expression were analyzed by RNAscope in situ hybridization and qRT-PCR.

Results: Blood glucose, HbA_1c and systolic blood pressure were unaffected by 2-week treatment of DM-HFD mice with finerenone. GLP-1R mRNA was detectable in vascular smooth muscle cells of kidney arterioles, and also present in juxtaglomerular apparatus cells, being sparse or absent in other kidney cells. Kidney GLP-1R mRNA levels were reduced in DM-HFD mice and this reduction was negated by finerenone (GLP-1R:RPL13A mRNA (fold) control 1.02±0.22, DM-HFD 0.67±0.09 (p<0.05 vs. control), DM-HFD + finerenone 1.10±0.34 (p<0.01 vs. DM-HFD)).

Conclusion: Kidney GLP-1R expression is diminished in aged mice with comorbid diabetes. This reduction is negated by treatment with the mineralocorticoid receptor antagonist finerenone. Both GLP-1R agonism and finerenone have demonstrated kidney protective benefits in people with diabetes. The present findings lend mechanistic support for the additive potential of combination therapy.