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Deregulated Renal Calcium and Phosphate Transport during Experimental Kidney Failure.

Pulskens WP, Verkaik M, Sheedfar F, van Loon EP, van de Sluis B, Vervloet MG, Hoenderop JG, Bindels RJ, NIGRAM Consorti - PLoS ONE (2015)

Bottom Line: Our results demonstrated that both experimental models induce features of CKD, as reflected by uremia, and elevated renal neutrophil gelatinase-associated lipocalin (NGAL) expression.In accordance, CKD augmented systemic PTH and affected the FGF23-αklotho-vitamin-D axis by elevating circulatory FGF23 levels and reducing renal αklotho expression.Moreover, this study identifies local tubular, possibly inflammation- or PTH- and/or FGF23-associated, adaptive mechanisms, impacting on Ca(2+)/Pi homeostasis, hence enabling new opportunities to target electrolyte disturbances that emerge as a consequence of CKD development.

View Article: PubMed Central - PubMed

Affiliation: Dept. of Physiology, Radboud University Medical Center, Nijmegen, The Netherlands.

ABSTRACT
Impaired mineral homeostasis and inflammation are hallmarks of chronic kidney disease (CKD), yet the underlying mechanisms of electrolyte regulation during CKD are still unclear. Here, we applied two different murine models, partial nephrectomy and adenine-enriched dietary intervention, to induce kidney failure and to investigate the subsequent impact on systemic and local renal factors involved in Ca(2+) and Pi regulation. Our results demonstrated that both experimental models induce features of CKD, as reflected by uremia, and elevated renal neutrophil gelatinase-associated lipocalin (NGAL) expression. In our model kidney failure was associated with polyuria, hypercalcemia and elevated urinary Ca(2+) excretion. In accordance, CKD augmented systemic PTH and affected the FGF23-αklotho-vitamin-D axis by elevating circulatory FGF23 levels and reducing renal αklotho expression. Interestingly, renal FGF23 expression was also induced by inflammatory stimuli directly. Renal expression of Cyp27b1, but not Cyp24a1, and blood levels of 1,25-dihydroxy vitamin D3 were significantly elevated in both models. Furthermore, kidney failure was characterized by enhanced renal expression of the transient receptor potential cation channel subfamily V member 5 (TRPV5), calbindin-D28k, and sodium-dependent Pi transporter type 2b (NaPi2b), whereas the renal expression of sodium-dependent Pi transporter type 2a (NaPi2a) and type 3 (PIT2) were reduced. Together, our data indicates two different models of experimental kidney failure comparably associate with disturbed FGF23-αklotho-vitamin-D signalling and a deregulated electrolyte homeostasis. Moreover, this study identifies local tubular, possibly inflammation- or PTH- and/or FGF23-associated, adaptive mechanisms, impacting on Ca(2+)/Pi homeostasis, hence enabling new opportunities to target electrolyte disturbances that emerge as a consequence of CKD development.

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FGF23 administration directly affected renal tubular calcium transport.(A) Intravenous administration of recombinant FGF23 protein (dark-gray bars) results in increased TRPV5 and a tendency towards elevated calbindin-D28k renal mRNA expression, when compared to vehicle-treated mice (white bars). Renal EGFP mRNA expression, as a surrogate marker for TRPV5 transcription tended to be increased following FGF23 administration compared to vehicle-treated mice. (B) Representative immunoblot and (C) semi-quantitative analysis of EGFP (B; upper panel) and β-actin (B; lower panel) protein expression in renal lysates of vehicle-treated or FGF23 injected mice. Blood (D) Ca2+ and (E) phosphate levels were measured following 24 hrs of FGF23 injection. (F) mRNA expression of the renal NaPi2a and NaPi2b in mice injected with FGF23 (gray bars), compared to vehicle-treated mice (white bars). Data are mean ± SEM. *: p<0.05 compared to control mice.
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pone.0142510.g006: FGF23 administration directly affected renal tubular calcium transport.(A) Intravenous administration of recombinant FGF23 protein (dark-gray bars) results in increased TRPV5 and a tendency towards elevated calbindin-D28k renal mRNA expression, when compared to vehicle-treated mice (white bars). Renal EGFP mRNA expression, as a surrogate marker for TRPV5 transcription tended to be increased following FGF23 administration compared to vehicle-treated mice. (B) Representative immunoblot and (C) semi-quantitative analysis of EGFP (B; upper panel) and β-actin (B; lower panel) protein expression in renal lysates of vehicle-treated or FGF23 injected mice. Blood (D) Ca2+ and (E) phosphate levels were measured following 24 hrs of FGF23 injection. (F) mRNA expression of the renal NaPi2a and NaPi2b in mice injected with FGF23 (gray bars), compared to vehicle-treated mice (white bars). Data are mean ± SEM. *: p<0.05 compared to control mice.

Mentions: To gain insight whether inflammatory stimuli directly affect renal Ca2+ handling, TRPV5 mRNA expression was determined in WT mice following ConA or TNF administration. ConA, but not TNF administration resulted in elevated renal TRPV5 mRNA expression (S1B Fig). Furthermore, to determine whether FGF23 affects renal Ca2+ handling, total kidney tissue of transgenic mice, expressing EGFP driven by the TRPV5 promoter, was used to determine mRNA expression of TRPV5, calbindin-D28k and EGFP, as a surrogate marker for TRPV5 transcription. Exogenous FGF23 administration resulted in an increased renal mRNA expression of TRPV5 (Fig 6A; P<0.05) and a tendency towards increased calbindin-D28k expression (Fig 6A). In addition, EGFP mRNA expression tended to be elevated following FGF23 infusion, although not statistically significant, when compared to control mice (Fig 6A).


Deregulated Renal Calcium and Phosphate Transport during Experimental Kidney Failure.

Pulskens WP, Verkaik M, Sheedfar F, van Loon EP, van de Sluis B, Vervloet MG, Hoenderop JG, Bindels RJ, NIGRAM Consorti - PLoS ONE (2015)

FGF23 administration directly affected renal tubular calcium transport.(A) Intravenous administration of recombinant FGF23 protein (dark-gray bars) results in increased TRPV5 and a tendency towards elevated calbindin-D28k renal mRNA expression, when compared to vehicle-treated mice (white bars). Renal EGFP mRNA expression, as a surrogate marker for TRPV5 transcription tended to be increased following FGF23 administration compared to vehicle-treated mice. (B) Representative immunoblot and (C) semi-quantitative analysis of EGFP (B; upper panel) and β-actin (B; lower panel) protein expression in renal lysates of vehicle-treated or FGF23 injected mice. Blood (D) Ca2+ and (E) phosphate levels were measured following 24 hrs of FGF23 injection. (F) mRNA expression of the renal NaPi2a and NaPi2b in mice injected with FGF23 (gray bars), compared to vehicle-treated mice (white bars). Data are mean ± SEM. *: p<0.05 compared to control mice.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4643984&req=5

pone.0142510.g006: FGF23 administration directly affected renal tubular calcium transport.(A) Intravenous administration of recombinant FGF23 protein (dark-gray bars) results in increased TRPV5 and a tendency towards elevated calbindin-D28k renal mRNA expression, when compared to vehicle-treated mice (white bars). Renal EGFP mRNA expression, as a surrogate marker for TRPV5 transcription tended to be increased following FGF23 administration compared to vehicle-treated mice. (B) Representative immunoblot and (C) semi-quantitative analysis of EGFP (B; upper panel) and β-actin (B; lower panel) protein expression in renal lysates of vehicle-treated or FGF23 injected mice. Blood (D) Ca2+ and (E) phosphate levels were measured following 24 hrs of FGF23 injection. (F) mRNA expression of the renal NaPi2a and NaPi2b in mice injected with FGF23 (gray bars), compared to vehicle-treated mice (white bars). Data are mean ± SEM. *: p<0.05 compared to control mice.
Mentions: To gain insight whether inflammatory stimuli directly affect renal Ca2+ handling, TRPV5 mRNA expression was determined in WT mice following ConA or TNF administration. ConA, but not TNF administration resulted in elevated renal TRPV5 mRNA expression (S1B Fig). Furthermore, to determine whether FGF23 affects renal Ca2+ handling, total kidney tissue of transgenic mice, expressing EGFP driven by the TRPV5 promoter, was used to determine mRNA expression of TRPV5, calbindin-D28k and EGFP, as a surrogate marker for TRPV5 transcription. Exogenous FGF23 administration resulted in an increased renal mRNA expression of TRPV5 (Fig 6A; P<0.05) and a tendency towards increased calbindin-D28k expression (Fig 6A). In addition, EGFP mRNA expression tended to be elevated following FGF23 infusion, although not statistically significant, when compared to control mice (Fig 6A).

Bottom Line: Our results demonstrated that both experimental models induce features of CKD, as reflected by uremia, and elevated renal neutrophil gelatinase-associated lipocalin (NGAL) expression.In accordance, CKD augmented systemic PTH and affected the FGF23-αklotho-vitamin-D axis by elevating circulatory FGF23 levels and reducing renal αklotho expression.Moreover, this study identifies local tubular, possibly inflammation- or PTH- and/or FGF23-associated, adaptive mechanisms, impacting on Ca(2+)/Pi homeostasis, hence enabling new opportunities to target electrolyte disturbances that emerge as a consequence of CKD development.

View Article: PubMed Central - PubMed

Affiliation: Dept. of Physiology, Radboud University Medical Center, Nijmegen, The Netherlands.

ABSTRACT
Impaired mineral homeostasis and inflammation are hallmarks of chronic kidney disease (CKD), yet the underlying mechanisms of electrolyte regulation during CKD are still unclear. Here, we applied two different murine models, partial nephrectomy and adenine-enriched dietary intervention, to induce kidney failure and to investigate the subsequent impact on systemic and local renal factors involved in Ca(2+) and Pi regulation. Our results demonstrated that both experimental models induce features of CKD, as reflected by uremia, and elevated renal neutrophil gelatinase-associated lipocalin (NGAL) expression. In our model kidney failure was associated with polyuria, hypercalcemia and elevated urinary Ca(2+) excretion. In accordance, CKD augmented systemic PTH and affected the FGF23-αklotho-vitamin-D axis by elevating circulatory FGF23 levels and reducing renal αklotho expression. Interestingly, renal FGF23 expression was also induced by inflammatory stimuli directly. Renal expression of Cyp27b1, but not Cyp24a1, and blood levels of 1,25-dihydroxy vitamin D3 were significantly elevated in both models. Furthermore, kidney failure was characterized by enhanced renal expression of the transient receptor potential cation channel subfamily V member 5 (TRPV5), calbindin-D28k, and sodium-dependent Pi transporter type 2b (NaPi2b), whereas the renal expression of sodium-dependent Pi transporter type 2a (NaPi2a) and type 3 (PIT2) were reduced. Together, our data indicates two different models of experimental kidney failure comparably associate with disturbed FGF23-αklotho-vitamin-D signalling and a deregulated electrolyte homeostasis. Moreover, this study identifies local tubular, possibly inflammation- or PTH- and/or FGF23-associated, adaptive mechanisms, impacting on Ca(2+)/Pi homeostasis, hence enabling new opportunities to target electrolyte disturbances that emerge as a consequence of CKD development.

Show MeSH
Related in: MedlinePlus