Energy-dense diets increase FGF23, lead to phosphorus retention and promote vascular calcifications in rats

Abstract

Rats with normal renal function (Experiment 1, n = 12) and uninephrectomized (1/2Nx) rats (Experiment 2, n = 12) were fed diets with normal P (NP) and either normal (NF) or high fat (HF). Rats with intact renal function (Experiment 3, n = 12) were also fed NF or HF diets with high P (HP). Additionally, uremic (5/6Nx) rats (n = 16) were fed HP diets with NF or HF. Feeding the HF diets resulted in significant elevation of plasma FGF23 vs rats fed NF diets: Experiment 1, 593 ± 126 vs 157 ± 28 pg/ml (p < 0.01); Experiment 2, 538 ± 105 vs 250 ± 18 pg/ml (p < 0.05); Experiment 3, 971 ± 118 vs 534 ± 40 pg/ml (p < 0.01). Rats fed HF diets showed P retention and decreased renal klotho (ratio klotho/actin) vs rats fed NF diets: Experiment 1, 0.75 ± 0.06 vs 0.97 ± 0.02 (p < 0.01); Experiment 2, 0.69 ± 0.07 vs 1.12 ± 0.08 (p < 0.01); Experiment 3, 0.57 ± 0.19 vs 1.16 ± 0.15 (p < 0.05). Uremic rats fed HF diet showed more severe vascular calcification (VC) than rats fed NF diet (aortic Ca = 6.3 ± 1.4 vs 1.4 ± 0.1 mg/g tissue, p < 0.001). In conclusion, energy-rich diets increased plasma levels of FGF23, a known risk factor of cardiovascular morbidity and mortality. Even though FGF23 has major phosphaturic actions, feeding HF diets resulted in P retention, likely secondary to decreased renal klotho, and aggravated uremic VC.

Vitamin E protects against extraskeletal calcification in uremic rats fed high fat diets

“…Our results confirm previous data showing that preconditioning with HF diet predisposes rats to develop extraskeletal calcifications associated to renal failure [ 10 ]. This finding highlights the potential deleterious effect on VC of energy-dense diets, even in the absence of obesity.…”

“…Prior to Nx, rats fed HF diets had very low plasma calcitriol concentrations. A decrease in plasma calcitriol, without changes in plasma calcidiol, has been previously reported in rats with normal renal function after feeding HF diets [ 10 ]. Since FGF23 is known to decrease calcitriol synthesis through inhibition of 1-alpha-hydroxylase activity in the kidney [ 17 ], these low calcitriol concentrations have been linked to the increase in FGF23 elicited by HF diets [ 10 ].…”

“…A decrease in plasma calcitriol, without changes in plasma calcidiol, has been previously reported in rats with normal renal function after feeding HF diets [ 10 ]. Since FGF23 is known to decrease calcitriol synthesis through inhibition of 1-alpha-hydroxylase activity in the kidney [ 17 ], these low calcitriol concentrations have been linked to the increase in FGF23 elicited by HF diets [ 10 ]. In uremic rats calcitriol should be further reduced by the decrease in renal mass and by the elevation in FGF23 secondary to kidney disease [ 18 ].…”

“…Moreover, we have recently shown that uremic rats fed high fat (HF) diets also develop more severe VC than their counterparts fed normal fat (NF) diets. Phosphorus (P) retention, secondary to renal klotho and fibroblast growth factor 23 (FGF23) dysregulation, seems to be implicated in the procalcifying effect of HF diet [ 10 ]. In patients with CKD, elevated serum P plays a major role in the development of VC [ 11 ].…”

Regulation of fibroblast growth factor 23 (FGF23) in health and disease

“…A diet rich in high fats elevates the serum FGF23 level in rodents , at least in part through enhanced inflammation .…”