#133 Effects of FGF23 on renal inflammation in an experimental model of diet-induced obesity: influence of sex

Abstract Background and Aims Increased levels of fibroblast growth factor 23 (FGF23) are associated with worsening renal function, increased risk of mortality and, independently, with increased inflammatory markers. On the other hand, obesity is also associated with direct renal damage through inflammatory alterations. Moreover, the potential involvement of FGF23 in clinical renal inflammation in the context of obesity may be different according to sex. In this study, we have determined the effects of FGF23 administration in an experimental model of diet-induced obesity that included mice of both sexes. Method Juvenile male and female C57BL/6J mice were fed with control diet (n = 16) or high-fat diet (HFD) (n = 16) 15 weeks. At week 14, half of each diet-group was administered intraperitoneal doses of recombinant FGF23 (70 ng/g/2 days), while the other half (control group) received an equal volume of PBS. At week 15, the animals were sacrificed and differences in renal expression of tumor necrosis factor α (Tnf), interleukin 6 (IL6), transforming growth factor beta 1 (Tfgß1) and nuclear factor NF-kappa-B 1 (Nfkb1) were analyzed. Differences in renal gene expression and immunoreactivity values for protein Klotho (Kl) were also determined. Results Treatment with recombinant FGF23 was associated with increased renal gene expression of cytokines Tnf and IL6, as well as NfKb1 and Tgfb1, independently of diet. However, these differences were only significant in females, with increases over 70% for Tnf and IL6 values and 100% for Tfgß1 and Nfkb1 (P < 0.01 in all cases). On the other hand, females showed significantly lower levels of Kl compared to males, both in gene expression and in their immunoreactivity (P < 0.01 for both cases). Conclusion These data suggest the existence of a differential effect of FGF23 on renal inflammation depending on sex which is independent of the presence of obesity. Differences in renal Kl expression depending on sex could play an important role in these effects.