FO051Glycogen synthase kinases 3-α/β inhibition attenuates progression of diabetic kidney disease beyond treatment with metformin/Ramipril/empagliflozin
Abstract
INTRODUCTION: There is an increasing prevalence of obesity-related type 2 diabetes and its complications. Treatment of diabetic kidney disease (DKD) by dual RAS and SGLT-2 blockade has profound effects on DKD progression, but further improvements are needed. Glycogen synthase kinases (GSK) 3-α/β inhibitors, such as BIO, have been shown to improve outcomes on non-diabetic injury by enhancing podocyte regeneration from local progenitors. We hypothesized that BIO would also improve outcomes of a clinically meaningful model of DKD. METHODS: Male BKS-Lepr-/- mice (DB) and non-diabetic BKS-Lepr+/+ controls (WT) underwent 2/4 nephrectomy (1K) at 6 weeks of age (week -2). To accelerate CKD progression, 1K mice were fed a sodium-deficient diet (“salt paradox” in DM) from week 0-16. 1K mice were treated from week 12-16 with a standard-of-care (SOC) therapy (1500mg/kg metformin, 6mg/kg ramipril, 480mg/kg empagliflozin) +/- BIO. Primary endpoint: GFR was measured using MediBeacon NIC in unrestricted animals. Secondary endpoints: Body weight (BW), blood glucose (BG) and albuminuria (ACR). After sacrifice, glomerular tuft area and podocyte density were quantified in cortical and juxtamedullary glomeruli. RESULTS: In DB mice, GFR increased after surgery and decreased along the weeks (A). Combination of SOC+BIO demonstrated an improvement on DKD progression in terms of delta GFR (difference between week 12 and week 16)(B). Additionally, the week-to-30% reduction in GFR was calculated in DB…
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