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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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Partial nephrectomy and adenine-enriched dietary treatment induced CKD.Mice subjected to (A) partial nephrectomy (5/6Nx; n = 9) after 3 weeks and (B) adenine-enriched dietary treatment (ADE; n = 5) for either 2 or 4 weeks display elevated blood urea levels, when compared to sham-operated (n = 5) or control mice (n = 5), respectively. Renal expression of tubular injury marker NGAL is significantly elevated in (C) 5/6Nx mice and (D) ADE mice after 2 and 4 weeks, compared to sham-operated or control mice, respectively. Data are mean ± SEM. *: p<0.05 compared to either sham-operated or control mice.
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pone.0142510.g001: Partial nephrectomy and adenine-enriched dietary treatment induced CKD.Mice subjected to (A) partial nephrectomy (5/6Nx; n = 9) after 3 weeks and (B) adenine-enriched dietary treatment (ADE; n = 5) for either 2 or 4 weeks display elevated blood urea levels, when compared to sham-operated (n = 5) or control mice (n = 5), respectively. Renal expression of tubular injury marker NGAL is significantly elevated in (C) 5/6Nx mice and (D) ADE mice after 2 and 4 weeks, compared to sham-operated or control mice, respectively. Data are mean ± SEM. *: p<0.05 compared to either sham-operated or control mice.

Mentions: The experimental models of partial nephrectomy (5/6Nx) and adenine-enriched dietary (ADE) treatment both induced renal failure. This is reflected by elevated blood urea levels in 5/6Nx mice compared to sham-operated mice after 3 weeks (Fig 1A) and the progressive uraemia observed in ADE mice when compared to control mice (Fig 1B). In addition, renal mRNA expression of tubular injury marker neutrophil gelatinase-associated lipocalin (NGAL) was increased 12-fold in kidney tissue of 5/6Nx mice and >500-fold in ADE-treated mice (Fig 1C and 1D). Moreover, mice subjected to either 5/6Nx or ADE treatment developed severe polyuria compared to sham-operated or control mice, respectively (Table 1).


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)

Partial nephrectomy and adenine-enriched dietary treatment induced CKD.Mice subjected to (A) partial nephrectomy (5/6Nx; n = 9) after 3 weeks and (B) adenine-enriched dietary treatment (ADE; n = 5) for either 2 or 4 weeks display elevated blood urea levels, when compared to sham-operated (n = 5) or control mice (n = 5), respectively. Renal expression of tubular injury marker NGAL is significantly elevated in (C) 5/6Nx mice and (D) ADE mice after 2 and 4 weeks, compared to sham-operated or control mice, respectively. Data are mean ± SEM. *: p<0.05 compared to either sham-operated or control mice.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0142510.g001: Partial nephrectomy and adenine-enriched dietary treatment induced CKD.Mice subjected to (A) partial nephrectomy (5/6Nx; n = 9) after 3 weeks and (B) adenine-enriched dietary treatment (ADE; n = 5) for either 2 or 4 weeks display elevated blood urea levels, when compared to sham-operated (n = 5) or control mice (n = 5), respectively. Renal expression of tubular injury marker NGAL is significantly elevated in (C) 5/6Nx mice and (D) ADE mice after 2 and 4 weeks, compared to sham-operated or control mice, respectively. Data are mean ± SEM. *: p<0.05 compared to either sham-operated or control mice.
Mentions: The experimental models of partial nephrectomy (5/6Nx) and adenine-enriched dietary (ADE) treatment both induced renal failure. This is reflected by elevated blood urea levels in 5/6Nx mice compared to sham-operated mice after 3 weeks (Fig 1A) and the progressive uraemia observed in ADE mice when compared to control mice (Fig 1B). In addition, renal mRNA expression of tubular injury marker neutrophil gelatinase-associated lipocalin (NGAL) was increased 12-fold in kidney tissue of 5/6Nx mice and >500-fold in ADE-treated mice (Fig 1C and 1D). Moreover, mice subjected to either 5/6Nx or ADE treatment developed severe polyuria compared to sham-operated or control mice, respectively (Table 1).

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