Presenting Author:

Samantha Neuburg, M.S.

Principal Investigator:

Aline Martin, Ph.D.

Department:

Medicine

Keywords:

Chronic Kidney Disease, FGF23, Left Ventricular Hypertrophy, Genetic Background, Col4a3 knockout mouse

Location:

Third Floor, Feinberg Pavilion, Northwestern Memorial Hospital

B57 - Basic Science

Chronic FGF23 Excess Induces LVH in a Model of CKD

An increased level of fibroblast growth factor (FGF)-23 is the earliest detectable sign of disordered mineral metabolism in chronic kidney disease (CKD), and a powerful risk factor for left ventricular hypertrophy (LVH), heart failure and death. Experimental models of CKD with elevated FGF23 and LVH are needed. We hypothesized that slower rates of CKD progression in the Col4a3KO mouse model of CKD would increase exposure to elevated FGF23 and promote development of LVH. We backcrossed 129X1/SvJ-Col4a3KO with C57Bl6/J mice and generated congenic Col4a3KO and WT with a mixed background including 75% 129X1/SvJ (129Sv) or 94% C57Bl6/J (B6) genomes. We compared overall survival and assessed renal function, FGF23 levels and cardiac morphology in WT controls and Col4a3KO with advanced CKD: at 10 weeks in the 129Sv, 20 weeks in the B6 mice. B6-Col4a3KO lived significantly longer than 129Sv-Col4a3KO (22±1 vs. 11±1 weeks; p<0.05). Ten week-old 129Sv-Col4a3KO showed impaired renal function (BUN: 191±39 vs. 34±4 mg/dL), hyperphosphatemia (serum Pi: 14.1±1.4 vs. 6.8±0.3 mg/dL) and a 33-fold increase in serum FGF23 levels (p<0.05 vs. WT for each). At 20 weeks, B6-Col4a3KO showed a similar but milder phenotype with impaired renal function (BUN: 85±17 vs. 24±3 mg/dL), hyperphosphatemia (Pi: 8.9±0.8 vs. 6.2±0.4 mg/dL) and an 8-fold increase in FGF23 levels (p<0.05 vs. WT for each), consistent with slower rates of CKD progression compared to 129Sv-Col4a3KO mice. Interestingly, 129Sv-Col4a3KO showed a ~2-fold increased mRNA expression of markers of cardiac fibrosis (Col3a1, Col1a2, Timp1) and altered cardiac function (Ejection Fraction (EF): 49.9±3.5 vs. 55.9±3.1 %) (p<0.05 vs. WT for each). Twenty week-old B6-Col4a3KO also displayed cardiac fibrosis, however they showed normal EF and were the only ones that presented LVH with increased LV Mass (125±3 vs. 98±6 mg) and ~2 to 4 fold increased mRNA expression of markers of cardiac hypertrophy (ANP, BNP, β-MHC) (p<0.05 vs. WT for each). The genetic background of the Col4a3KO mouse influences its rate of CKD progression, cardiac phenotype and survival. Slower CKD progression and longer survival are associated with development of LVH in B6-Col4a3KO, which can serve as a novel model of cardiorenal disease. Whether LVH is mediated, in part, by longer exposure of B6-Col4a3KO mice to elevated FGF23 levels requires further study.