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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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Progression of CKD altered FGF23-αklotho signalling.Experimental CKD deregulates FGF23-αklotho signalling as reflected by (A) a tendency towards elevated circulatory FGF23 levels in 5/6Nx mice and (B) progressively elevated FGF23 levels in ADE treated mice compared to control mice. Renal mRNA expression of FGFR1 and αKlotho in (C) CKD induced 5/6Nx mice (black bars) compared with sham-operated groups (white bars) and in (D) 2 weeks (black bars) and 4 weeks (gray bars) ADE treated mice compared with control groups (white bars). (E) Representative immunoblot (all 3 groups are done in one blot) and (F) semi-quantitative analysis for αKlotho (E; upper panel) and β-actin (E; lower panel) protein expression in renal lysates of control or ADE treated mice, which indicates reduced renal αKlotho protein expression upon CKD. Data are mean ± SEM. *: p<0.05 compared to control mice.
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pone.0142510.g002: Progression of CKD altered FGF23-αklotho signalling.Experimental CKD deregulates FGF23-αklotho signalling as reflected by (A) a tendency towards elevated circulatory FGF23 levels in 5/6Nx mice and (B) progressively elevated FGF23 levels in ADE treated mice compared to control mice. Renal mRNA expression of FGFR1 and αKlotho in (C) CKD induced 5/6Nx mice (black bars) compared with sham-operated groups (white bars) and in (D) 2 weeks (black bars) and 4 weeks (gray bars) ADE treated mice compared with control groups (white bars). (E) Representative immunoblot (all 3 groups are done in one blot) and (F) semi-quantitative analysis for αKlotho (E; upper panel) and β-actin (E; lower panel) protein expression in renal lysates of control or ADE treated mice, which indicates reduced renal αKlotho protein expression upon CKD. Data are mean ± SEM. *: p<0.05 compared to control mice.

Mentions: In order to determine whether induced kidney failure results in altered FGF23-αklotho signalling, we first measured blood FGF23 levels. FGF23 levels tended to be elevated in 5/6Nx mice when compared to sham-operated mice (Fig 2A), and progressively increased in ADE mice compared to control mice (Fig 2B; P<0.05). 5/6Nx did not affect renal mRNA expression of the primary FGF23 receptor FGFR1, while αklotho expression tended to be decreased, although not statistically significant (Fig 2C). ADE-treated mice demonstrated a mild raise in FGFR1 (after 4 weeks) and a progressive (>2-fold) reduction in renal αklotho mRNA expression (Fig 2D; P<0.05 for both time points) when compared to control mice. In addition, a 2-fold decline in renal αklotho expression following ADE treatment was confirmed on protein level (Fig 2E and 2F; P<0.05 for both time points).


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)

Progression of CKD altered FGF23-αklotho signalling.Experimental CKD deregulates FGF23-αklotho signalling as reflected by (A) a tendency towards elevated circulatory FGF23 levels in 5/6Nx mice and (B) progressively elevated FGF23 levels in ADE treated mice compared to control mice. Renal mRNA expression of FGFR1 and αKlotho in (C) CKD induced 5/6Nx mice (black bars) compared with sham-operated groups (white bars) and in (D) 2 weeks (black bars) and 4 weeks (gray bars) ADE treated mice compared with control groups (white bars). (E) Representative immunoblot (all 3 groups are done in one blot) and (F) semi-quantitative analysis for αKlotho (E; upper panel) and β-actin (E; lower panel) protein expression in renal lysates of control or ADE treated mice, which indicates reduced renal αKlotho protein expression upon CKD. 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.g002: Progression of CKD altered FGF23-αklotho signalling.Experimental CKD deregulates FGF23-αklotho signalling as reflected by (A) a tendency towards elevated circulatory FGF23 levels in 5/6Nx mice and (B) progressively elevated FGF23 levels in ADE treated mice compared to control mice. Renal mRNA expression of FGFR1 and αKlotho in (C) CKD induced 5/6Nx mice (black bars) compared with sham-operated groups (white bars) and in (D) 2 weeks (black bars) and 4 weeks (gray bars) ADE treated mice compared with control groups (white bars). (E) Representative immunoblot (all 3 groups are done in one blot) and (F) semi-quantitative analysis for αKlotho (E; upper panel) and β-actin (E; lower panel) protein expression in renal lysates of control or ADE treated mice, which indicates reduced renal αKlotho protein expression upon CKD. Data are mean ± SEM. *: p<0.05 compared to control mice.
Mentions: In order to determine whether induced kidney failure results in altered FGF23-αklotho signalling, we first measured blood FGF23 levels. FGF23 levels tended to be elevated in 5/6Nx mice when compared to sham-operated mice (Fig 2A), and progressively increased in ADE mice compared to control mice (Fig 2B; P<0.05). 5/6Nx did not affect renal mRNA expression of the primary FGF23 receptor FGFR1, while αklotho expression tended to be decreased, although not statistically significant (Fig 2C). ADE-treated mice demonstrated a mild raise in FGFR1 (after 4 weeks) and a progressive (>2-fold) reduction in renal αklotho mRNA expression (Fig 2D; P<0.05 for both time points) when compared to control mice. In addition, a 2-fold decline in renal αklotho expression following ADE treatment was confirmed on protein level (Fig 2E and 2F; P<0.05 for both time points).

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