FP410AN optimized animal model of progressive CKD in type 2 diabetes to improve predictability of preclinical drug testing
Abstract
INTRODUCTION AND AIMS: The discrepancy between the design of preclinical studies and randomized clinical trials (RCT) may be one reason why RCTs often do not replicate preclinical findings, especially in “diabetic nephropathy”. We hypothesized that an animal model more closely mimicking the target population of “diabetic nephropathy” RCTs can close this gap and improve predictability. Thus, we defined the following animal model criteria: 1) type 2 diabetes mellitus (T2DM); 2) obesity as a cofactor for CKD progression; 3) standard-of-care (SOC) treatment including antidiabetic drug, RAS and SGLT2 inhibition; 4) increasing albuminuria; and 5) CKD G3 with progressive decline in GFR. METHODS: We decided for male BKS-db/db mice with insulin resistance and profound obesity even on normal diet (T2DM). CKD was induced either by 2/4 or 3/4 nephrectomy (UNx or 3/4Nx) at 6 weeks of age (week -2). To further accelerate CKD progression, UNx mice were fed a sodium-deficient diet (“salt paradox” in DM). GFR was measured using MediBeacon NIC in awake and unrestricted animals. At week 10, 3/4Nx mice and some of UNx mice were sacrificed to perform histological analysis. Some UNx mice were treated with a triple SOC therapy (metformin, ramipril, empagliflozin) from week 12-16. RESULTS: Body weight in 3/4Nx mice increased along the experiment (A). 3/4Nx db/db mice lost hyperglycemia after the surgery (B), as a result of impaired intrarenal insulin breakdown suggested by higher plasma C-peptide…
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