Abstract MP16: ReninAAV Uninephrectomized db/db Mice as a Novel Diabetic Kidney Diesease Model for Testing New Therapeutics on Top of RAS Inhibition
ReninAAV comprises a novel approach to induce persistent hypertension in diverse murine models. ReninAAV induced hypertension is persistent and facilitates the development of animal models of diseases accelerated or driven by hypertension such as diabetic kidney disease (DKD). A single injection of ReninAAV (5x109 GC) in uninephrectomized (uNx) db/db mice results in progressive DKD. Impaired renal function was detected as early as one week post injection with an 8.9±3.1-fold increase in ACR (albumin:creatinine) as compared to baseline values, and at 11 weeks post injection significantly (p<0.01) increased serum creatinine (0.20±0.03mg/dL) and ACR were detected (68,890±7,209μg/mg) versus LacZAAV uNx db/db controls (0.08±0.01mg/dL and 1,364±83μg/mg, respectively). To determine if treatment with the ACEi Linsinopril halted progression of renal disease uNx db/db were given ReninAAV and followed for 4 weeks until ACR reached approximately 15,000μg/mg. Mice were randomized into 4 treatment groups: untreated, Lisinopril low (30mg/L), Lisinopril medium (100mg/L) and Lisinopril high (300mg/L) and followed for an additional 8 weeks. Untreated mice showed progressive increase in ACR developing a final ACR of 35,318±4,177μg/mg. Lisinopril dose dependently reduced ACR significantly compared to baseline (p<0.001, final ACR of 7,869±1632, 2,730±582 and 2,014±44μg/mg for the 30, 100 and 300 mg/L groups respectively), albeit still elevated compared to control LacZAAV uNx db/db mice (1,364±831μg/mg) that did not receive ReninAAV. Lisinopril treatment at 100 and 300mg/L also resulted in improvement in final serum creatinine values (p<0.05, 0.18±0.01 and 0.14±0.01mg/dL respectively vs untreated ReninAAV group 0.26±0.03mg/dL), yet residual increased serum creatinine were apparent compared to control LacZAAV uNx db/db mice (0.08±0.012mg/dL). This study establishes ReninAAV treated uNx db/db mice as a novel model of progressive DKD and demonstrates that suppression of RAS with Lisinopril improved, but only partially prevented progression of renal disease, thus enabling testing of new potential therapeutics on top of RAS inhibition.
Author Disclosures: S.M. Harlan: A. Employment; Significant; Eli Lilly and Company. H.E. Baker: A. Employment; Significant; Eli Lilly and Company. C.R. Shrake: A. Employment; Significant; Eli Lilly and Company. M.D. Breyer: A. Employment; Significant; Eli Lilly and Company. J.G. Heuer: A. Employment; Significant; Eli Lilly and Company.
- © 2015 by American Heart Association, Inc.