Genetic background influences cardiac phenotype in murine chronic kidney disease

Background. Levels of fibroblast growth factor 23 (FGF23) increase early in chronic kidney disease (CKD) and are inde- pendently associated with left ventricular hypertrophy (LVH), heart failure and death. Experimental models of CKD with ele- vated FGF23 and LVH are needed. We hypothesized that slow rates of CKD progression in the Col4a3 knockout (Col4a3KO) mouse model of CKD would promote development of LVH by prolonging exposure to elevated FGF23. Methods. We studied congenic Col4a3KO and wild-type (WT) mice with either 75% 129X1/SvJ (129Sv) or 94% C57Bl6/J (B6) genomes. Results. B6-Col4a3KO lived longer than 129Sv-Col4a3KO mice (21.460.6 versus 11.460.4weeks; P<0.05). 10-week-old 129Sv-Col4a3KO mice showed impaired renal function (blood urea nitrogen 191639 versus 3464mg/dL), hyperphosphate- mia (14.161.4 versus 6.860.3mg/dL) and 33-fold higher serum FGF23 levels (P<0.05 versus WT for each). Consistent with their slower CKD progression, 10week-old B6-Col4a3KO mice showed milder impairment of renal function than 129Sv- Col4a3KOmice andmodest FGF23 elevation without other alter- ations of mineral metabolism. At 20weeks, further declines in renal functioninB6-Col4a3KOmice was accompanied by hyper- phosphatemia and 8-fold higher FGF23 levels (P<0.05 versus WT for each). Only the 20-week-old B6-Col4a3KO mice devel- oped LVH (LV mass 12563 versus 9866mg; P<0.05 versus WT) in association with significantly increased cardiac expres- sion of FGF receptor 4 (FGFR4) messenger RNA and protein and markers of LVH (Atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP), beta-myosin heavy chain (b-MHC); P<0.05 versusWT for each). Conclusions. In conclusion, B6-Col4a3KO mice manifest slower CKD progression and longer survival than 129Sv-Col4a3KO mice and can serve as a novelmodel of cardiorenal disease.