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. 2018 Feb 26;8(1):3590.
doi: 10.1038/s41598-018-22041-1.

Elevated FGF23 Levels in Mice Lacking the Thiazide-Sensitive NaCl cotransporter (NCC)

Ganesh Pathare  1   2   3 , Manuel Anderegg  4   5   6 , Giuseppe Albano  4   5   6 , Florian Lang  7   8 , Daniel G Fuster  4   5   6
Affiliations

Elevated FGF23 Levels in Mice Lacking the Thiazide-Sensitive NaCl cotransporter (NCC)

Ganesh Pathare et al. Sci Rep. .

Abstract

Fibroblast growth factor 23 (FGF23) participates in the orchestration of mineral metabolism by inducing phosphaturia and decreasing the production of 1,25(OH)2D3. It is known that FGF23 release is stimulated by aldosterone and extracellular volume depletion. To characterize this effect further in a model of mild hypovolemia, we studied mice lacking the thiazide sensitive NaCl cotransporter (NCC). Our data indicate that NCC knockout mice (KO) have significantly higher FGF23, PTH and aldosterone concentrations than corresponding wild type (WT) mice. However, 1,25(OH)2D3, fractional phosphate excretion and renal brush border expression of the sodium/phosphate co-transporter 2a were not different between the two genotypes. In addition, renal expression of FGF23 receptor FGFR1 and the co-receptor Klotho were unaltered in NCC KO mice. FGF23 transcript was increased in the bone of NCC KO mice compared to WT mice, but treatment of primary murine osteoblasts with the NCC inhibitor hydrochlorothiazide did not elicit an increase of FGF23 transcription. In contrast, the mineralocorticoid receptor blocker eplerenone reversed excess FGF23 levels in KO mice but not in WT mice, indicating that FGF23 upregulation in NCC KO mice is primarily aldosterone-mediated. Together, our data reveal that lack of renal NCC causes an aldosterone-mediated upregulation of circulating FGF23.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
Blood concentrations of cFGF23, iFGF23, PTH and 1,25(OH)2D3 in WT and NCC KO mice. Arithmetic means ± SEM (n = 9–12) of serum cFGF23 (a), serum iFGF23 (b), plasma PTH (c) and serum 1,25(OH)2D3 (d) in WT (grey bars) and NCC KO (black bars) under normal diet. *(p < 0.05) indicates significant difference from NCC WT mice.
Figure 2
Figure 2
FGF23 mRNA levels in femora of WT and NCC KO mice. Arithmetic means ± SEM (n = 6–8) of FGF23 mRNA levels in femora obtained from WT (black bars) and NCC KO mice (grey bars) under normal diet. **(p < 0.01) indicates significant difference from NCC WT mice.
Figure 3
Figure 3
Blood and urinary phosphate (Pi), calcium (Ca) and magnesium (Mg) in WT and NCC KO mice. (a–c) Arithmetic means ± SEM (n = 9–12) of serum Pi (a), Ca (b) and Mg (c) in WT (black bars) and NCC KO mice (grey bars) under normal diet. (d–f) Arithmetic means ± SEM (n = 9–12) of urinary Pi (d), Ca (e) and Mg (f) normalized with creatinine in WT (black bars) and NCC KO mice (grey bars) under normal diet. *(p < 0.05) indicates significant difference from WT mice.
Figure 4
Figure 4
Brush border abundance of Napi2a and renal expression of α-Klotho and FGFR1. (a) Original western blot of Napi2a and beta actin in BBM isolated from NCC WT and KO kidneys. Quantification of Napi2a expression in WT and KO kidneys. (b) Original western blot of α-Klotho, FGFR1 and beta actin in total kidney lysate from NCC WT and KO kidneys. Quantification of α-Klotho and FGFR1 expression in WT and KO kidneys.
Figure 5
Figure 5
Effect of hydrochlorothiazide (HCT) treatment on FGF23 expression in murine primary osteoblast. Arithmetic means ± SEM (n = 5–6) of FGF23 mRNA levels in murine primary osteoblasts following treatment with vehicle (ethanol; control), 10 nM 1,25(OH)2D3 or 1, 10, 100 μM HCT. *(p < 0.05) for ctrl vs 1,25(OH)2D3, HCT 1, 10, 100 μM. FGF23 transcript levels are expressed relative to the level of the GAPDH control gene.
Figure 6
Figure 6
Effect of eplerenone on circulating aldosterone, cFGF23 and iFGF23 levels. (a–c) Arithmetic means ± SEM (n = 6–7) of serum aldosterone (a), serum cFGF23 (b), and serum iFGF23 (c) in NCC WT mice NCC KO under baseline and following oral eplerenone treatment for 7 days (right bars). *(p < 0.05) indicates significant difference from NCC WT mice, #(p < 0.05) indicates significant difference from eplerenone diet.
Figure 7
Figure 7
Effect of dietary phosphate depletion on blood and urinary electrolytes and circulating cFGF23, iFGF23 and PTH levels in WT and NCC KO mice. (a–f) Arithmetic means ± SEM (n = 6–7) of serum phosphate (a), Ca (b) and Mg (c) levels. Serum cFGF23 (d), serum iFGF23 (e), and plasma PTH (f) in NCC WT mice (grey bars) and NCC KO (black bars) under normal diet (Ctrl diet, left bars) and following dietary phosphate depletion for 5 days (LPD, right bars). *(p < 0.05) indicates significant difference from NCC WT mice, #(p < 0.05) indicates significant difference from normal diet. (g,h) Arithmetic means ± SEM (n = 6–7) of urinary phosphate excretion (g) and urinary calcium excretion (h) in NCC KO and wild type mice under normal diet (Day 0) and following dietary phosphate depletion (Day 1–5). *(p < 0.05), **(p < 0.01) indicate significant difference from NCC WT mice.
Figure 8
Figure 8
Effect of dietary phosphate depletion on blood and urinary electrolytes and circulating aldosterone levels in WT and NCC KO mice: (a–c) Arithmetic means ± SEM (n = 6–7) of serum aldosterone (a), Na (b) and K (c) levels in NCC WT mice (black bars) and NCC KO (grey bars) under normal diet (Ctrl diet, left bars) and following dietary phosphate depletion for 5 days (LPD, right bars). *(p < 0.05) indicates significant difference from NCC WT mice, #(p < 0.05) indicates significant difference from normal diet. (d–f) Arithmetic means ± SEM (n = 6–7) of urinary Na excretion (d) urinary K excretion (e) and the ratio of urinary Na to K excretion (f) in NCC KO and WT mice under normal diet (Day 0) and following dietary phosphate depletion (Day 1–5). *(p < 0.05) indicate significant difference from NCC WT mice.
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