Kidney fibroblast growth factor 23 does not contribute to elevation of its circulating levels in uremia

Abstract

Fibroblast growth factor 23 (FGF23) secreted by osteocytes is a circulating factor essential for phosphate homeostasis. High plasma FGF23 levels are associated with cardiovascular complications and mortality. Increases of plasma FGF23 in uremia antedate high levels of phosphate, suggesting a disrupted feedback regulatory loop or an extra-skeletal source of this phosphatonin. Since induction of FGF23 expression in injured organs has been reported we decided to examine the regulation of FGF23 gene and protein expressions in the kidney and whether kidney-derived FGF23 contributes to the high plasma levels of FGF23 in uremia. FGF23 mRNA was not detected in normal kidneys, but was clearly demonstrated in injured kidneys, already after four hours in obstructive nephropathy and at 8 weeks in the remnant kidney of 5/6 nephrectomized rats. No renal extraction was found in uremic rats in contrast to normal rats. Removal of the remnant kidney had no effect on plasma FGF23 levels. Well-known regulators of FGF23 expression in bone, such as parathyroid hormone, calcitriol, and inhibition of the FGF receptor by PD173074, had no impact on kidney expression of FGF23. Thus, the only direct contribution of the injured kidney to circulating FGF23 levels in uremia appears to be reduced renal extraction of bone-derived FGF23. Kidney-derived FGF23 does not generate high plasma FGF23 levels in uremia and is regulated differently than the corresponding regulation of FGF23 gene expression in bone.

Parathyroid Hormone, Fibroblast Growth Factor 23, and Parameters of Phosphate Reabsorption

“…In normal rodents, these authors showed that kidneys removed FGF23 from the renal circulation [17]. In rats subjected to 5/6 nephrectomy, they found that renal arterial and venous concentrations of FGF23 were comparable even though renal synthesis of FGF23 was demonstrable, and concluded that net renal addition of FGF23 to the circulation had not occurred [18]. The authors also documented FGF23 gene transcription in skeletons of animals receiving normal- or high-phosphate diets.…”

“…Total parathyroidectomy eliminated FGF23 gene transcription in bone, and it greatly reduced plasma [FGF23]. The authors concluded that PTH promoted skeletal synthesis of FGF23 in rodents with remnant kidneys, and high [FGF23] resulted from decreased renal extraction of the hormone [18]. …”

“…In patients with reduced GFR, we propose that increased [P] CDN interferes with the effect of PTH on calcium reabsorption and thereby necessitates high [PTH] for maintenance of normocalcemia [4, 10, 13]. PTH and other stimuli increase skeletal synthesis of FGF23 [18-22], and [FGF23] rises because renal extraction of the hormone is compromised [18]. The reason that [FGF23] rises before [PTH] in patients with CKD may be that hepatic metabolism of PTH continues apace as renal extraction of FGF23 falls [23].…”

TGF-Beta Signaling in Bone with Chronic Kidney Disease

“…In uremic animals, renal FGF23 expression correlates with local TGF-β1 expression [112]. Smith et al demonstrated that FGF23 augments FGFR4 activation and upregulation of the calcium transporter in the absence of klotho, leading to enhanced TGF-β1 autoinduction through increases of both intracellular calcium and mitochondrial reactive oxygen species [113].…”

Fibroblast Growth Factor-23: A Novel Biomarker for Cardiovascular Disease in Chronic Kidney Disease Patients

“…However, the role of kidney as a probable extraskeletal source of FGF-23 remains controversial. Thus, induced expression of FGF-23 has been reported in animal models of CKD [9,10] whereas a very recent study showed that kidney FGF-23 does not contribute to elevation of its circulating levels in uremia [11].…”